University of Groningen Towards personalized management of drug interactions: from drug-drug-interaction to drug- drug-gene-interaction Bahar, Akbar

(1)

Towards personalized management of drug interactions: from interaction to

drug-drug-gene-interaction

Bahar, Akbar

DOI:

10.33612/diss.112160601

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Publication date:

2020

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Bahar, A. (2020). Towards personalized management of drug interactions: from drug-drug-interaction to

drug-drug-gene-interaction. University of Groningen. https://doi.org/10.33612/diss.112160601

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(2)

Pharmacogenetics of Drug-Drug-Interaction (DDI)

and Drug-Drug-Gene-Interaction (DDGI):

a Systematic Review on CYP2C9, CYP2C19, and CYP2D6

Muh. Akbar Bahar

Didik Setiawan

Eelko Hak

Bob Wilffert

(3)

pharmacogenetics on DDI and DDGI in which three major drug-metabolizing enzymes - CYP2C9,

CYP2C19, and CYP2D6 - are central. We observed that several DDI and DDGI are highly

gene-dependent, leading to a different magnitude of interaction. Precision drug therapy should take

pharmacogenetics into account when drug interactions in clinical practice are expected.

(4)

6 pharmacodynamically by a co-administered drug

3

_{. With respect to the metabolic interactions, drugs}

which affect cytochrome P450 (CYP450) isoenzymes are commonly involved and prevalent in clinical

practice

4-7

_{. Importantly, CYP450 isoenzymes are subject to genetic polymorphism}

8

_{. Therefore, since}

the functionality of CYP450 isoenzymes is crucial to the impact of DDIs, polymorphism can affect

their magnitude

9,10

_.

The pharmacogenetic impact on the interaction between drug and CYP450 isoenzymes

(drug-gene interaction) has been incorporated in some guidelines

11-13

_{. However, these guidelines do not}

consider any change in the magnitude of the drug-gene interaction (DGI) for different CYP450

isoenzyme genotypes after co-administration of a drug affecting those isoenzymes. Therefore, this

interplay is rarely considered in clinical practice, and systematic evidence about such important

pharmacogenetic effects on DDIs is lacking.

Furthermore, an even more complicated interaction can develop in drugs metabolized by several

CYP450 isoenzymes

14

_{. There will be a marked alteration in the pharmacokinetics of the drugs if all of}

their metabolic pathways are blocked by CYP450 isoenzyme inhibitors

15-18

_{. Polymorphism also plays}

a role in the metabolism of drugs with multiple metabolic pathways

19

_{. The genetic polymorphism in}

their major metabolic pathway and the inhibition of their minor metabolic pathway could result in

a significant change to their plasma concentration. This overlapping of DDI and DGI conditions is

referred to as drug-drug-gene-interaction (DDGI)

20

_{. In a retrospective analysis of 1143 genotyped}

patients in the US with 1053 clinically relevant drug interactions, DDGIs were reported to occur in

about 19%. DDIs and DGIs accounted for 66% and 15%, respectively

20

_{. An updated cross-sectional}

study from the US involving 22,885 patients found that there were about 16,900 clinically relevant

drug interactions in which DDGIs, DGIs, and DDIs accounted for 22%, 25%, and 53%, respectively

21

_.

The complexity of DDGIs results in a greater variability in drug level than DDI and DGI. To the best of

our knowledge, no systematic review has compiled all the relevant studies regarding the effect of

pharmacogenetics of DDGIs involving CYP450 isoenzymes.

To prevent CYP450-mediated drug interactions, a computerized surveillance tool is

incorporated in the majority of health record systems

22

_{. Since pharmacogenetics testing is not}

yet part of routine clinical testing, the effect of genetic variations in DDI and DDGI have not been

considered in such surveillance system

23,24

_{. Therefore, the aim of this review is to describe the impact}

of pharmacogenetics on DDIs and DDGIs involving three major drug-metabolizing enzymes -

CYP2C9, CYP2C19, and CYP2D6. The results may further support the improvement of the quality of

computerized surveillance systems and enhance precision drug therapy.

Method

The systematic review was structured according to PRISMA (Preferred Reporting Items for

Systematic Reviews and Meta-analyses)

25

_{. Studies published before November 2015 from the Pubmed}

(5)

6 case studies involving CYP2D6/CYP2C9/CYP2C19 mediated drug interaction published in English in

the peer-reviewed literature were eligible. The DDI group included articles comparing the effect of

DDIs in different genotypes and/or phenotypes. The DDGI group consisted of articles presenting

data about DDIs mediated at least by two enzymes, one of which (CYP2D6/CYP2C19/CYP2C9) had

a deviating genotype and/or phenotype, while the activity of another enzyme was influenced by

an effector drug. We also performed a reference tracking process to include eligible studies which

were not retrieved in our systematic search.

Data Abstraction

The extracted papers were screened by two independent reviewers (MAB and DS) based on

the eligibility criteria. Conflicting results were discussed by MAB and DS. A third reviewer (BW)

was involved if no consensus was reached. The review process was performed by screening

the title and abstract. The results were then evaluated by full-text screening. The relevant

information such as pharmacokinetics and/or pharmacodynamics data; study type; name, drug

type and dose; number and type of patients; and genotype and/or phenotype data were collected.

The strength of the evidence (0 to 4) was also evaluated independently by MAB and DS using

the previously published criteria (Supplement 1)

11,24

_{. The differences in the scoring of evidence}

level were resolved by consensus involving BW. The magnitude of interactions was estimated

based on changes in pharmacokinetic values using the criteria provided by Verbeurgt et al. and

Polasek et al. (Supplement 1)

4,20

_{. The availability of the pharmacodynamics data could change}

the categorization of the interaction. If the substrate had a narrow therapeutic index, the level of

the interactions was upgraded to a level above their categories based on their pharmacokinetic

value assessments

20

_{. The categorization of the interaction was structured based on its impact and}

whether an action should be taken to manage it as suggested by Van Roon et al.: Interaction: Yes/

Action: Yes, Interaction: Yes/Action: No and Interaction: No/Action: No

24

_{. If there was at least one}

genotype with a major (contraindicated interaction) or substantial (needing monitoring or dose

adjustment) interaction, we categorized it as Interaction: Yes/Action: Yes. If the maximum impact of

the interactions in the genotype subset was moderate (possible interaction/no action required), we

categorized it as Interaction: Yes/Action: No. Lastly, if the genotype subset only had a minimal (not

clinically significant) interaction, we categorized it as Interaction: No/Action: No. Some aspects

should be considered in this clinical assessment. Firstly, using data from one study with only few

patients or healthy volunteers constrained offering a comprehensive judgement about the clinical

interpretation of interactions. Secondly, some interactions were between effector drugs and probe

substrates, therefore, the assessment could be viewed as an estimate of the potency of effector

drugs as inhibitors or inducers.

(6)

6 After title and abstract screening, 243 of 4,108 articles were included for full paper screening.

After removing the irrelevant articles (144 articles) and adding eligible articles from the reference

tracking (6 articles), 66 and 39 articles reporting evidence for DDIs and DDGIs, respectively, were

chosen for data abstraction. The main reasons for exclusion included: only reporting on DGI,

no genotype comparisons, no interaction and that the interactions between genotypes were

hardly differentiated.

Genotype data

The genotypes were grouped with the phenotypes based on the ‘Royal Dutch Association

for the Advancement of Pharmacy’ (KNMP) categorization and adjusted in concordance to

the standardized terms provided by the Clinical Pharmacogenetics Implementation Consortium i.e.

Normal Metabolizer (NM), Intermediate Metabolizer (IM), Poor Metabolizer (PM), Rapid Metabolizer

(RM) and Ultrarapid Metabolizer (UM)

26,27

_{. NM of CYP2C9 included CYP2C91/1. IM of CYP2C9 included}

CYP2C91/2; CYP2C91/3. PM of CYP2C9 included CYP2C92/2; CYP2C92/3; CYP2C93/3. NM of

CYP2C19 included CYP2C191/1. IM of CYP2C19 included CYP2C191/2; CYP2C191/3. PM of CYP2C19

included CYP2C192/2; CYP2C192/3; CYP2C193/3. RM of CYP2C19 included CYP2C191/17. UM of

CYP2C19 included CYP2C1917/17. NM of CYP2D6 included CYP2D61/1; CYP2D61/2; CYP2D62/2;

CYP2D61/10; CYP2D61/41; CYP2D62/10; CYP2D62/41. IM of CYP2D6 included CYP2D61/3;

CYP2D61/4; CYP2D61/5; CYP2D61/6; CYP2D61/21; CYP2D62/3; CYP2D62/4; CYP2D62/5;

CYP2D610/41; CYP2D610/10; CYP2D63/41; CYP2D64/41; CYP2D65/10; CYP2D66/10;

CYP2D66/41; CYP2D610/21; CYP2D610/30. PM of CYP2D6 included CYP2D63/4; CYP2D64/4;

CYP2D64/5; CYP2D64/6; CYP2D65/5; CYP2D65/16; CYP2D67/7. UM of CYP2D6 included

CYP2D61/1xN; CYP2D61/2xN; CYP2D61/4xN; CYP2D61/41xN; CYP2D62/2xN.

Pharmacogenetics of Drug-Drug Interaction (DDI)

CYP2C9

Interaction: Yes/Action: Yes

There were five scenarios of CYP2C9 mediated DDI producing clinically significant interactions

(Table 1). First, co-administration of CYP2C9 substrates in patients with CYP2C9 variant alleles

produced a competitive inhibition, as shown for Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

and coumarin interactions. Since both of them are CYP2C9 substrates, NSAIDs appeared to

further decrease coumarin metabolism in patients with decreased CYP2C9 activities. Therefore,

NSAIDs elevated the risk of over-anticoagulation in coumarin-treated CYP2C91/2 and

CYP2C91/3 patients

28,29

_.

Second, a CYP2C9*3 selective inhibition aggravated the metabolic interference due to genetic

polymorphism as presented in warfarin and simvastatin interaction. Warfarin was less metabolized

by CYP2C93, and specific inhibition of CYP2C93 by simvastatin caused an even larger impairment

(7)

6

Fi g ur e 1. T he s ch em e and n um b er o f p ap er s at e ach s te p o f t he s ys te m at ic r ev ie w .

(8)

6 Third, the magnitude of interaction depended on the CYP2C9 activity as observed in fluconazole

and flurbiprofen interactions

31

_{. Fluconazole inhibited flurbiprofen metabolism more profoundly in}

normal metabolizers (NMs) and intermediate metabolizers (IMs) than in poor metabolizers (PMs)

of CYP2C9. The increase of the dose of fluconazole from 200 mg to 400 mg enhanced its inhibitory

capacity, indicated by a twofold increase of the AUC (Area Under Curve) value in NMs and IMs but

not in PMs. The reduced function of CYP2C9*3 caused insusceptibility towards the inhibition in PMs.

However, there was still an inhibition of fluconazole in PMs because fluconazole (at a dose ≥200 mg)

may inhibit the remaining metabolic pathways of flurbiprofen (CYP3A4/2C19)

32

_.

Fourth, the capacity of a CYP2C9 inhibitor, which was also a substrate of the enzyme, to impair

the metabolism of a CYP2C9 substrate was correlated with its plasma concentration in different

genotypes. It was considered in valproic acid and losartan interaction

33

_{. Patients with CYP2C9*3}

had a higher plasma concentration of valproic acid compared to those with other genotypes.

Consequently, valproic acid produced a greater magnitude of inhibition in losartan metabolism in

this group.

Fifth, the greatest increase in CYP2C9 activity after administration of an inducer was in

CYP2C93/3 as demonstrated in rifampicin and tolbutamide combinations

34

_{. There was a six-fold}

difference in the baseline activity of CYP2C91/1 and CYP2C93/3 in metabolizing tolbutamide

34

_{. It,}

therefore, seems that the greater the CYP2C9 activity, the smaller the induction magnitude produced

by rifampicin. The underlying mechanism of this negative correlation should be investigated further.

Additionally, rifampicin showed a comparable induction capacity to other genotypes. This could be

due to the involvement of the P-glycoprotein (P-gp) transport system, since rifampicin is an inducer

of this transporter. But there was no evidence for this speculation reported in the study.

Interaction: Yes/Action: No

The only study in this group was a gene-dependent interaction between phenytoin and losartan

35

_.

Phenytoin moderately inhibited losartan metabolism in CYP2C91/1 but not in CYP2C91/2.

However, this result was hardly justified since there were only two CYP2C91/2 subjects in the study.

CYP2C19

Interaction: Yes/Action: Yes

CYP2C19-mediated DDIs engage a different magnitude of interaction in different genotypes as

demonstrated by various interaction scenarios (Table 1). The first scenario was a competitive

inhibition between two CYP2C19 substrates due to segregation of a metabolic pathway in normal

but not in slow CYP2C19 metabolizers. Polymorphism in the IMs and PMs diminished the metabolic

function of CYP2C19. Competitive binding to this isoenzyme was thus hardly emerged. It was

observed in the combination of Proton Pump Inhibitors (PPIs) and clopidogrel. Omeprazole and

rabeprazole, but not lansoprazole, significantly affected clopidogrel efficacy in NMs but not in

(9)

6 affinity to CYP2C19, had a comparable potency as omeprazole. This could be because rabeprazole

was metabolized by CYP2C19 along with its non-enzymatic metabolite, rabeprazole thioether,

rabeprazole thus generated a stronger competitive inhibition than lansoprazole to clopidogrel

37

_.

Further, PPIs attenuated the clopidogrel effect more profoundly in CYP2C1917 than CYP2C192,

and CYP2C19*1 homozygotes carriers

38

_{. Since CYP2C19*17 is related to the increased activity, it}

appeared that the larger contribution of CYP2C19 in the bio-conversion of clopidogrel, the bigger

alteration was produced by PPIs.

A competitive inhibitory mechanism was also found in the PPI-warfarin interaction. Patients

with CYP2C19 IM using lansoprazole and warfarin concomitantly had a greater incidence of

haemorrhagic complications than NMs and PMs

39

_{. The combination of polymorphism and inhibition}

by lansoprazole yielded a reduction of warfarin metabolism causing an increased risk of bleeding. In

addition, Uno et al. reported that omeprazole inhibited R-warfarin metabolism, but not S-warfarin

(CYP2C9 substrate) metabolism, only in NMs

40

_{. Therefore, CYP2C19 is one of the factors determining}

the effectiveness of warfarin.

The second scenario was phenoconversion of the CYP2C19 NM genotype to the PM phenotype

as presented by ticlopidine and omeprazole interaction

42

_{. Ticlopidine strongly inhibited omeprazole}

metabolism in NMs and IMs producing pharmacokinetic values to the level of PMs (Supplement 2).

However, PMs were not affected. The gene-dependent interaction was also shown by moclobemide

and omeprazole, which produced a substantial interaction in NMs but not in PMs

43

_{. Moreover,}

CYP2C19 inhibition by moclobemide produced an increase of omeprazole sulphone concentration

(omeprazole metabolite via CYP3A4) indicating the metabolic shifting of omeprazole from CYP2C19

to CYP3A4. The affinity of omeprazole to CYP2C19 is ten times greater than to CYP3A4

14

_{. The latter}

contributes 13 to 22% to omeprazole metabolism

44

_{. However, when CYP2C19 is inhibited, CYP3A4}

may have a greater metabolic contribution.

The third scenario was an inhibitor and substrate of multi CYP450 isoenzyme interaction as

illustrated by fluvoxamine (CYP2C9/2C8/1A2/2C19/3A4 inhibitor) and PPIs combination

14,41,45-47

_.

The highest influence of fluvoxamine on PPIs metabolism was observed in NMs, followed by IMs

and then PMs. Omeprazole and lansoprazole produced a greater magnitude of interactions with

fluvoxamine than rabeprazole for all genotypes, because rabeprazole only involves CYP2C19 in

its metabolism while omeprazole and lansoprazole involve CYP2C19/3A4. Fluvoxamine thus had

a greater impact on omeprazole and lansoprazole than rabeprazole since their bimodal metabolic

pathways were affected. It seems that if the effector drug can inhibit several of the CYP isoenzymes

responsible for drug metabolism, it will produce a greater magnitude interaction

14

_.

The fourth scenario was that CYP2C19 inhibition involved NMs predominantly, but with less

pronounced CYP2C19 isoenzymes with increased activities, as indicated by oral contraceptives

(OC) and omeprazole interaction

48

_{. OC impaired the omeprazole metabolism by substantially}

(10)

6 a drug but with its metabolite. It was demonstrated by the interaction between sulthiame and an

active metabolite of clobazam (mainly by CYP3A4), N-desmethyl-clobazam (DMCLB)

49

_{. DMCLB was}

metabolized by CYP2C19, and co-administration of sulthiame enhanced the concentration/dose

(C/D) ratio of DMCLB substantially in NMs and IMs. Although the anti-seizure effect of DMCLB was

less than clobazam, the significant increase of its concentration after sulthiame administration, may

increase its efficacy as well as its side-effects

49

_.

The last scenario was the interaction of a CYP2C19 inducer and substrate as observed in rifampicin

and mephenytoin combination

50

_{. The largest increase of 4-hydroxymephenytoin excretion,}

a product of mephenytoin hydroxylation by CYP2C19, was in NMs. However, rifampicin produced

comparable induction in IMs and PMs, probably because of non-CYP2C19 hydroxylase induction

50

_.

Interaction: Yes/Action: No

The first scenario was a competitive inhibition between two CYP2C19 substrates as presented by

clopidogrel and omeprazole interaction

51

_{. In this interaction, clopidogrel became an inhibitor}

distinct from the previously explained major interaction where clopidogrel acted as a substrate.

Clopidogrel moderately inhibited omeprazole metabolism in NMs but not in PMs. There was an

increase of omeprazole sulfone concentration in NMs after clopidogrel treatment indicating

the CYP3A4 buffer mechanism. However, after clopidogrel co-administration, the amount of

omeprazole sulfone remained at the same level meaning that clopidogrel did not inhibit CYP3A4.

Comparable cases were observed when the inhibitory effect of omeprazole was examined

against moclobemide and diazepam. Omeprazole competitively inhibited the metabolism of

moclobemide via CYP2C19 and diazepam via CYP2C19/3A4 to produce moderate impact in NMs

but not in PMs

52-54

_{. Diazepam is also metabolized by CYP2B6. The CYP2C19/3A4 inhibition may}

shift diazepam metabolism to CYP2B6

14

_{. Consequently, the interaction only produced a moderate}

impact since diazepam still had a metabolic pathway remaining. The final scenario was the

gene-dependent interaction between a CYP2C19 inhibitor and a substrate as observed in fluvoxamine

and chloroguanide combination

55

_{. Fluvoxamine moderately inhibited the biotransformation of}

chloroguanide to cycloguanil and 4-chlorphenylbiguanide in NMs, and minimally in PMs.

CYP2D6

Interaction: Yes/Action: Yes

CYP2D6 with polymorphism are perturbed to different DDI magnitudes than with normal metabolic

activity, as implied in several interaction scenarios (Table 1). First, the interaction between

CYP2D6 inhibitors and substrates only involved patients with functional CYP2D6, as presented in

dextromethorphan and CYP2D6 inhibitors (terbinafine, perhexiline, and quinidine) interactions

(Figure 2)

56-59

_{. CYP2D6 inhibitors produced significant interactions with dextromethorphan in NMs}

(11)

6

CYP2C9

Interaction: Yes/Action: Yes

29 NSAID Coumarins CYP2C9*1 (normal) The risk of over-anticoagulation

(INR ≥ 6) = 1.69 (95% CI, 1.05-2.69) NA Substantial Reduced capacity of CYP2C9; CYP2C9 inhibition 3 CYP2C9*2; CYP2C9*3 (decreased) The risk of over-anticoagulation

(INR ≥ 6) = 2.28 (95% CI, 1.06-4.90)

NA Major

28 NSAID

(Standard daily dose)

Acenocoumarol CYP2C9*1/*1 (NM) No significant increase in INRs

(INR < 4.9) NA Minimal Reduced capacity of CYP2C9; CYP2C9 inhibition 3

CYP2C9*1/*2;*1/*3 (IM) Significant increase in INRs (INR > 4.9) NA Major

30 Simvastatin Warfarin CYP2C9*1/*1 (NM) NA dose ↓5% Minimal Inhibition of

CYP2C9*3-dependent warfarin metabolism

3

CYP2C9*1/*2 (IM) NA dose ↓5% Minimal

CYP2C9*1/*3 (IM) NA dose ↓25% Substantial

CYP2C9*2/*2 (PM) NA dose ↓5% Minimal

CYP2C9*2/*3 (PM) NA dose ↓25% Substantial

31 Fluconazole (200 mg)

Flurbiprofen (50 mg)

CYP2C9*1/*1 (NM) NA AUC ↑102% Substantial CYP2C9

inhibition 3

CYP2C9*1/*3 (IM) NA AUC ↑79% Moderate

CYP2C9*3/*3 (PM) NA AUC ↑41% Moderate

Fluconazole (400 mg)

CYP2C9*1/*1 (NM) NA AUC ↑203% Substantial

CYP2C9*1/*3 (IM) NA AUC ↑148% Substantial

CYP2C9*3/*3 (PM) NA AUC ↑23% Minimal

33 Valproic Na

(1st_{week=200 mg& next 3}

weeks=400 mg) Losartan (25 mg) CYP2C9*1/*1 (NM) NA MR of losartan/ E3174 = 1.8. Ratio = 2.7. Substantial CYP2C9 inhibition 3

CYP2C9*1/*2 (IM) NA MR = 1.5. Ratio = 2.5. Substantial

34 Rifampicin (450 mg)

Tolbutamide (500 mg)

CYP2C9*1/*1 (NM) NA Clearance ↑97% Moderate CYP2C9

induction 3

CYP2C9*1/*2 (IM) NA Clearance ↑84% Moderate

CYP2C9*2/*3 (PM) NA Clearance ↑70% Moderate

CYP2C9*3/*3 (PM) NA Clearance ↑162% Substantial

IM genotype to a PM phenotype at a higher rate in individuals with one functional allele compared

to those with at least two functional alleles

57

_{. The gene-selective inhibition by quinidine was also}

found in combination with venlafaxine, mexiletine, brofaromine, methoxyphenamine, encainide,

procainamide, and flecainide

60-70

_{. Quinidine significantly changed the pharmacokinetic parameters}

of these substrates in NMs and IMs, but not in PMs. The pharmacodynamic parameters of this

gene-dependent interaction showed comparable results. Quinidine abolished the differences between

NMs and PMs in encainide-induced QRS and PR prolongation. The strong inhibitory potency of

quinidine can be corroborated by its ability to inhibit the P-gp transporter

58

_.

(12)

6

CYP2C9

29 NSAID Coumarins CYP2C9*1 (normal) The risk of over-anticoagulation

(INR ≥ 6) = 1.69 (95% CI, 1.05-2.69) NA Substantial Reduced capacity of CYP2C9; CYP2C9 inhibition 3 CYP2C9*2; CYP2C9*3 (decreased) The risk of over-anticoagulation

(INR ≥ 6) = 2.28 (95% CI, 1.06-4.90)

NA Major

28 NSAID

(Standard daily dose)

Acenocoumarol CYP2C9*1/*1 (NM) No significant increase in INRs

(INR < 4.9) NA Minimal Reduced capacity of CYP2C9; CYP2C9 inhibition 3

CYP2C9*1/*2;*1/*3 (IM) Significant increase in INRs (INR > 4.9) NA Major

30 Simvastatin Warfarin CYP2C9*1/*1 (NM) NA dose ↓5% Minimal Inhibition of

CYP2C9*3-dependent warfarin metabolism

3

CYP2C9*1/*2 (IM) NA dose ↓5% Minimal

CYP2C9*1/*3 (IM) NA dose ↓25% Substantial

CYP2C9*2/*2 (PM) NA dose ↓5% Minimal

31 Fluconazole (200 mg)

inhibition 3

CYP2C9*1/*3 (IM) NA AUC ↑79% Moderate

CYP2C9*3/*3 (PM) NA AUC ↑41% Moderate

Fluconazole (400 mg)

CYP2C9*1/*1 (NM) NA AUC ↑203% Substantial

CYP2C9*1/*3 (IM) NA AUC ↑148% Substantial

CYP2C9*3/*3 (PM) NA AUC ↑23% Minimal

33 Valproic Na

(1st_{week=200 mg& next 3}

weeks=400 mg) Losartan (25 mg) CYP2C9*1/*1 (NM) NA MR of losartan/ E3174 = 1.8. Ratio = 2.7. Substantial CYP2C9 inhibition 3

34 Rifampicin (450 mg)

Tolbutamide (500 mg)

CYP2C9*1/*1 (NM) NA Clearance ↑97% Moderate CYP2C9

induction

3

CYP2C9*2/*3 (PM) NA Clearance ↑70% Moderate

CYP2C9*3/*3 (PM) NA Clearance ↑162% Substantial

Paroxetine and quetiapine also inhibit the CYP2D6 and P-gp transporter

14

_{. Paroxetine produced}

a significant inhibition of flecainide, desipramine, aripiprazole and R-methadone metabolism

more profoundly in individuals with two active alleles than those with decreased or dysfunctional

alleles

71-75

_{. Similarly, quetiapine gene-dependently affected the R-methadone metabolism}

76

_{. These}

interactions generated pharmacodynamic effects in a comparable manner. Paroxetine significantly

changed the QT interval of flecainide-treated NMs but not IMs

72

_{. However, amiodarone and}

(13)

6

Interaction: Yes/Action: No 35 Phenytoin (4 mg/kg) Losartan (50 mg)

CYP2C9*1/*1 (NM) NA AUC↑ 29% Moderate CYP2C9

inhibition 3

CYP2C9*1/*2 (IM) NA AUC↓ 30% Minimal

CYP2C19

36 Omeprazole (20 mg) Clopidogrel (75 mg) CYP2C19*1/*1 (NM) ADP-Ag = 45.7%± 14.2% (p = 0.028 vs alone) NA Major CYP2C19 inhibition 3

CYP2C19*1/*2;*1/*3 (IM) ADP-Ag = 47.2% ± 13.1%

( p = 0.085 vs alone) NA Minimal CYP2C19*2/*2;*2/*3 (PM) ADP-Ag = 53.9% ±13.0 % (p = 0.864 vs alone) NA Minimal 37 Omeprazole (20 mg) Clopidogrel (75 mg)

CYP2C19*1/*1 (NM) IPA = 51.2% (P = 0.015 vs alone) NA Major CYP2C19

inhibition 3

CYP2C19*1/*2;*1/*3;*2/*3 (IM/PM) IPA = 33.3% (P = 0.443 vs alone) NA Minimal

Lansoprazole (30 mg)

Clopidogrel (75 mg)

CYP2C19*1/*1 (NM) IPA = 56.5% (P = 0.508 vs alone) NA Minimal

Rabeprazole (20 mg)

Clopidogrel (75 mg)

CYP2C19*1/*1 (NM) IPA = 53.5% (P = 0.035 vs alone) NA Substantial

38 Proton pump inhibitor (PPI) Clopidogrel CYP2C19*1/*1 (NM) Adjusted HR for 1-year cardiac

rehospitalization = 1.51 (0.90–2.54), P= 0.12 vs non PPI users

NA Minimal CYP2C19

inhibition 3

CYP2C19*2 carriers (decreased) Adjusted HR = 1.69 (0.95–2.99),

P=0.07vs non PPI users

NA Minimal

CYP2C19*17 carriers (Increased) Adjusted HR= 2.05 (1.26–3.33), P=0.003 vs non PPI users

NA Major 39 Lansoprazole (15 mg) Warfarin (Initial dose 3 mg) NM Incidence of hemorrhagic complications=2 cases (4.8%) NA Moderate CYP2C19 inhibition 3 IM Incidence = 6 cases (14.6%) (P=0.0172 vs NM& PM) NA Substantial

PM Incidence = 2 cases (4.8%) NA Moderate

40 Omeprazole (20 mg)

R-warfarin (10 mg)

CYP2C19*1/*1 (NM) PT-INR max = 1.62 (1.42-1.82).

P = 0.252 Vs. before

AUC ↑20% Substantial CYP2C19

inhibition 3

CYP2C19*2/*2;*2/*3 (PM) PT-INR max = 1.40(1.20-1.59).

P=0.263 Vs before

AUC ↓9% Minimal

S-warfarin (10 mg)

CYP2C19*1/*1 (NM) NA AUC ↑7% Moderate

CYP2C19*2/*2;*2/*3 (PM) NA AUC ↓7% Minimal

42 Ticlopidine (200 mg)

Omeprazole (20 mg)

CYP2C19*1/*1 (NM) NA AUC ↑522% Major CYP2C19

inhibition 3

CYP2C19*1/*2;*1/*3 (IM) NA AUC ↑401% Major

43 Moclobemide (300 mg)

Omeprazole (40 mg)

inhibition 3

(14)

6

Interaction: Yes/Action: No 35 Phenytoin (4 mg/kg) Losartan (50 mg)

CYP2C9*1/*1 (NM) NA AUC↑ 29% Moderate CYP2C9

inhibition

3

CYP2C9*1/*2 (IM) NA AUC↓ 30% Minimal

CYP2C19

36 Omeprazole (20 mg) Clopidogrel (75 mg) CYP2C19*1/*1 (NM) ADP-Ag = 45.7%± 14.2% (p = 0.028 vs alone) NA Major CYP2C19 inhibition 3

CYP2C19*1/*2;*1/*3 (IM) ADP-Ag = 47.2% ± 13.1%

( p = 0.085 vs alone) NA Minimal CYP2C19*2/*2;*2/*3 (PM) ADP-Ag = 53.9% ±13.0 % (p = 0.864 vs alone) NA Minimal 37 Omeprazole (20 mg) Clopidogrel (75 mg)

CYP2C19*1/*1 (NM) IPA = 51.2% (P = 0.015 vs alone) NA Major CYP2C19

inhibition

3

Clopidogrel (75 mg)

CYP2C19*1/*1 (NM) IPA = 56.5% (P = 0.508 vs alone) NA Minimal

Rabeprazole (20 mg)

Clopidogrel (75 mg)

CYP2C19*1/*1 (NM) IPA = 53.5% (P = 0.035 vs alone) NA Substantial

38 Proton pump inhibitor (PPI) Clopidogrel CYP2C19*1/*1 (NM) Adjusted HR for 1-year cardiac

rehospitalization = 1.51 (0.90–2.54), P= 0.12 vs non PPI users

NA Minimal CYP2C19

inhibition

3

CYP2C19*2 carriers (decreased) Adjusted HR = 1.69 (0.95–2.99),

P=0.07vs non PPI users

NA Minimal

CYP2C19*17 carriers (Increased) Adjusted HR= 2.05 (1.26–3.33), P=0.003 vs non PPI users

NA Major 39 Lansoprazole (15 mg) Warfarin (Initial dose 3 mg) NM Incidence of hemorrhagic complications=2 cases (4.8%) NA Moderate CYP2C19 inhibition 3 IM Incidence = 6 cases (14.6%) (P=0.0172 vs NM& PM) NA Substantial

PM Incidence = 2 cases (4.8%) NA Moderate

R-warfarin (10 mg)

CYP2C19*1/*1 (NM) PT-INR max = 1.62 (1.42-1.82).

P = 0.252 Vs. before

AUC ↑20% Substantial CYP2C19

inhibition

3

CYP2C19*2/*2;*2/*3 (PM) PT-INR max = 1.40(1.20-1.59).

P=0.263 Vs before

AUC ↓9% Minimal

S-warfarin (10 mg)

CYP2C19*1/*1 (NM) NA AUC ↑7% Moderate

42 Ticlopidine (200 mg)

Omeprazole (20 mg)

inhibition

3

43 Moclobemide (300 mg)

Omeprazole (40 mg)

inhibition

3

(15)

6

46 Fluvoxamine (50 mg)

Omeprazole (60 mg)

inhibition 3

CYP2C19*1/*2;*1/*3 (IM) NA AUC ↑138% Substantial

CYP2C19*2/*2;*2/*3 (PM) NA AUC ↑15% Minimal

inhibition 3

47 Fluvoxamine (25 mg bid)

R-lansoprazole (60 mg)

inhibition 3

CYP2C19*2/*2;*2/*3 (PM) NA AUC ↑127% Substantial

Fluvoxamine (25 mg bid)

S-lansoprazole (60 mg)

CYP2C19*1/*1 (NM) NA AUC ↑1297% Major

Rabeprazole (20 mg)

inhibition 3

CYP2C19*1/*2;*1/*3 (IM) NA AUC ↑68% Moderate

48 Oral contraceptives (OC) Omeprazole (20 mg) CYP2C19*1/*1 (NM) MR = 1.21 (0.71-2.08) (P < 0.05 vs without) NA Substantial CYP2C19 inhibition 3 CYP2C19*1/*17 (RM) MR = 0.77 (0.55-1.10) (P > 0.05 vs without) NA Minimal CYP2C19*17/*17 (UM) MR = 1.05 (0.54-2.04) (P > 0.05 vs without) NA Minimal

49 Sulthiame Clobazam CYP2C19*1/*1 (NM) NA C/D ratio of DMCLB ↑83% Substantial CYP2C19

inhibition 3

CYP2C19*1/*2 (IM) NA C/D ratio of DMCLB

↑198% Substantial 50 Rifampicin (300 mg) Racemic mephenytoin (100 mg)

CYP2C19*1/*1 (NM) NA Excretion of 4-OH-MP =

↑203.9±42.5%

Substantial CYP2C19 induction

3

CYP2C19*1/*2;*1/*3 (IM) NA Excretion of 4-OH-MP =

↑69.6±4.1%

Moderate

CYP2C19*2/*2; *2/*3 (PM) NA Excretion of 4-OH-MP =

↑80.1±48% Moderate Interaction: Yes/Action: No 51 Clopidogrel (Day 1=300 mg; Day 2-5=75 mg) Omeprazole (400 mg)

CYP2C19*1/*1 (NM) NA AUC ↑28% Moderate CYP2C19

inhibition 3

Moclobemide (300 mg)

NM NA AUC ↑31% Moderate CYP2C19

inhibition 3 PM NA AUC ↓2% Minimal 53 Omeprazole (20 mg) Diazepam (0.1mg/Kg)

inhibition 3 PM NA AUC ↓10% Minimal 54 Omeprazole (20 mg) Diazepam (0.1 mg/Kg)

inhibition 3

(16)

6

Omeprazole (60 mg)

inhibition

3

inhibition

3

47 Fluvoxamine (25 mg bid)

R-lansoprazole (60 mg)

inhibition

3

Fluvoxamine (25 mg bid)

S-lansoprazole (60 mg)

CYP2C19*1/*1 (NM) NA AUC ↑1297% Major

Rabeprazole (20 mg)

inhibition

3

CYP2C19*1/*2;*1/*3 (IM) NA AUC ↑68% Moderate

48 Oral contraceptives (OC) Omeprazole (20 mg) CYP2C19*1/*1 (NM) MR = 1.21 (0.71-2.08) (P < 0.05 vs without) NA Substantial CYP2C19 inhibition 3 CYP2C19*1/*17 (RM) MR = 0.77 (0.55-1.10) (P > 0.05 vs without) NA Minimal CYP2C19*17/*17 (UM) MR = 1.05 (0.54-2.04) (P > 0.05 vs without) NA Minimal

49 Sulthiame Clobazam CYP2C19*1/*1 (NM) NA C/D ratio of DMCLB ↑83% Substantial CYP2C19

inhibition

3

CYP2C19*1/*2 (IM) NA C/D ratio of DMCLB

↑198% Substantial 50 Rifampicin (300 mg) Racemic mephenytoin (100 mg)

CYP2C19*1/*1 (NM) NA Excretion of 4-OH-MP =

↑203.9±42.5%

Substantial CYP2C19 induction

3

CYP2C19*1/*2;*1/*3 (IM) NA Excretion of 4-OH-MP =

↑69.6±4.1%

Moderate

CYP2C19*2/*2; *2/*3 (PM) NA Excretion of 4-OH-MP =

↑80.1±48% Moderate Interaction: Yes/Action: No 51 Clopidogrel (Day 1=300 mg; Day 2-5=75 mg) Omeprazole (400 mg)

CYP2C19*1/*1 (NM) NA AUC ↑28% Moderate CYP2C19

inhibition

3

Moclobemide (300 mg)

inhibition 3 PM NA AUC ↓2% Minimal 53 Omeprazole (20 mg) Diazepam (0.1mg/Kg)

inhibition 3 PM NA AUC ↓10% Minimal 54 Omeprazole (20 mg) Diazepam (0.1 mg/Kg)

inhibition

3

(17)

6

Chloroguanide (200 mg)

NM NA Total CL↓39% Moderate CYP2C19

inhibition 3

PM NA Total CL↑20% Minimal

CYP2D6#

56 Terbinafine (250 mg)

Dextromethorphan (0.3 mg/kg)

CYP2D6*1/*1;*1/*2;*2/*2;*1/*4 (NM/IM) NA MR DMP/dextrorphan =

0.307, Absolute change = 96.67, (P<0.05 vs before) Major CYP2D6 inhibition 3 CYP2D6*4/*6;*4/*5;*5/*16 (PM) NA MR=0.803,Absolute change= 0.53 (P>0.05 vs before) Minimal 57 Perhexiline Dextromethorphan (16.4 mg) CYP2D6*1/*4;*1/*5;*2/*3;*2/*4;*1/*6 (IM) NA MR = 0.398 (P < 0.05 vs. control) Major CYP2D6 inhibition 3 CYP2D6*1/*1;*1/*2;*2/*2;*1/*1xN;*1/*2xN;*2/*2xN (NM/ UM) NA MR = 0.08 (P < 0.05 vs IMs) Moderate 59 Quinidine (50 mg qid) Dextromethorphan (50 mg)

NM NA AUC ↑329% Major CYP2D6

inhibition 3 PM NA AUC ↓12% Minimal 58 AVP-923 capsules (30 mg quinidine bid) Dextromethorphan (30 mg)

NM NA Mean MR = 0.80 ± 0.37 Major CYP2D6

inhibition 3 PM NA Mean MR = 1.86 ± 0.51 Minimal 65 Quinidine (100 mg bid) S-Venlafaxine (18.75 mg bid)

CYP2D6*1/*4;*1/*1 (NM/IM) NA AUC ↑285% Major CYP2D6

inhibition 3

CYP2D6*3/*4;*4/*4 (PM) NA AUC ↑15% Minimal

R-Venlafaxine (18.75 mg bid)

CYP2D6*1/*4;*1/*1 (NM/IM) NA AUC ↑1118% Major

CYP2D6*3/*4;*4/*4 (PM) NA AUC ↓1% Minimal

66 Quinidine (100 mg bid)

Venlafaxine (18.75 mg bid)

NM NA Oral CL ↓83% Major CYP2D6

inhibition 3 PM NA Oral CL ↓0% Minimal 60 Quinidine (50 mg qid) R-mexiletine (200 mg)

NM NA Total CL ↓32% Substantial CYP2D6

inhibition 3 PM NA Total CL ↑9% Minimal S-mexiletine (200 mg) NM NA Total CL ↓30% Substantial PM NA Total CL ↑4% Minimal 61 Quinidine (50 mg qid) Mexiletine (200 mg)

inhibition 3

PM NA Total CL ↓0.3% Minimal

68 Quinidine Brofaromine NM NA AUC ↑136% Substantial CYP2D6

inhibition 3 PM NA AUC ↓10% Minimal 67 Quinidine (250 mg) Methoxyphenamine (60.3 mg) NM NA Dose excreted in 0-32 h urine ↑103% Substantial CYP2D6 inhibition 3 PM NA Dose excreted in 0-32 h urine ↓0.4% Minimal 64 Quinidine (50 mg tid) Encainide (60 mg & 4.5 mg)

NM Quinidine abolished the differences

in encainide induced QRS & PR prolongation between NM & PM.

Total CL ↓76% Major CYP2D6

inhibition 3 PM Total CL ↓19% Minimal 69 Quinidine (50 mg qid) Procainamide (500 mg)

NM NA NAPA AUC = ↑30% Substantial CYP2D6

inhibition 3

(18)

6

Chloroguanide (200 mg)

NM NA Total CL↓39% Moderate CYP2C19

inhibition

3

PM NA Total CL↑20% Minimal

CYP2D6#

56 Terbinafine (250 mg)

Dextromethorphan (0.3 mg/kg)

CYP2D6*1/*1;*1/*2;*2/*2;*1/*4 (NM/IM) NA MR DMP/dextrorphan =

0.307, Absolute change = 96.67, (P<0.05 vs before) Major CYP2D6 inhibition 3 CYP2D6*4/*6;*4/*5;*5/*16 (PM) NA MR=0.803,Absolute change= 0.53 (P>0.05 vs before) Minimal 57 Perhexiline Dextromethorphan (16.4 mg) CYP2D6*1/*4;*1/*5;*2/*3;*2/*4;*1/*6 (IM) NA MR = 0.398 (P < 0.05 vs. control) Major CYP2D6 inhibition 3 CYP2D6*1/*1;*1/*2;*2/*2;*1/*1xN;*1/*2xN;*2/*2xN (NM/ UM) NA MR = 0.08 (P < 0.05 vs IMs) Moderate 59 Quinidine (50 mg qid) Dextromethorphan (50 mg)

NM NA AUC ↑329% Major CYP2D6

inhibition 3 PM NA AUC ↓12% Minimal 58 AVP-923 capsules (30 mg quinidine bid) Dextromethorphan (30 mg)

NM NA Mean MR = 0.80 ± 0.37 Major CYP2D6

inhibition 3 PM NA Mean MR = 1.86 ± 0.51 Minimal 65 Quinidine (100 mg bid) S-Venlafaxine (18.75 mg bid)

CYP2D6*1/*4;*1/*1 (NM/IM) NA AUC ↑285% Major CYP2D6

inhibition

3

CYP2D6*3/*4;*4/*4 (PM) NA AUC ↑15% Minimal

R-Venlafaxine (18.75 mg bid)

CYP2D6*1/*4;*1/*1 (NM/IM) NA AUC ↑1118% Major

CYP2D6*3/*4;*4/*4 (PM) NA AUC ↓1% Minimal

66 Quinidine (100 mg bid)

NM NA Oral CL ↓83% Major CYP2D6

inhibition 3 PM NA Oral CL ↓0% Minimal 60 Quinidine (50 mg qid) R-mexiletine (200 mg)

inhibition 3 PM NA Total CL ↑9% Minimal S-mexiletine (200 mg) NM NA Total CL ↓30% Substantial PM NA Total CL ↑4% Minimal 61 Quinidine (50 mg qid) Mexiletine (200 mg)

inhibition

3

PM NA Total CL ↓0.3% Minimal

68 Quinidine Brofaromine NM NA AUC ↑136% Substantial CYP2D6

inhibition 3 PM NA AUC ↓10% Minimal 67 Quinidine (250 mg) Methoxyphenamine (60.3 mg) NM NA Dose excreted in 0-32 h urine ↑103% Substantial CYP2D6 inhibition 3 PM NA Dose excreted in 0-32 h urine ↓0.4% Minimal 64 Quinidine (50 mg tid) Encainide (60 mg & 4.5 mg)

NM Quinidine abolished the differences

in encainide induced QRS & PR prolongation between NM & PM.

Total CL ↓76% Major CYP2D6

inhibition 3 PM Total CL ↓19% Minimal 69 Quinidine (50 mg qid) Procainamide (500 mg)

NM NA NAPA AUC = ↑30% Substantial CYP2D6

inhibition

3

(19)

6

70 Quinidine 50 mg qid R-flecainide (Low dose) NM a slight increase in

the pharmacodynamics effect (the mean of QRS & % arrhythmia suppression)

Metabolic CL ↓28% Substantial CYP2D6 inhibition 3 PM Metabolic CL ↑19% Minimal 71 Paroxetine (20 mg) Flecainide (200 mg)

CYP2D6*1/*1;*1/*2 (NM) NA AUC ↑28% Substantial CYP2D6

inhibition 3

CYP2D6*1/*10 (NM) NA AUC ↑16% Moderate

CYP2D6*10/*10;*10/*30 (IM) NA AUC ↓2% Minimal

72 Paroxetine (20 mg)

Flecainide (200 mg)

CYP2D6*1/*1;*1/*2 (NM) Change in QTcF, msec = 6.5 (3.2-9.8)

P=0.002

NA Substantial CYP2D6

inhibition 3

CYP2D6*1/*10 (NM) Change in QTcF, msec = 6.7 (3.6-9.7)

P=0.001

NA Substantial

CYP2D6*10/*10;*10/*30 (IM) Change in QTcF, msec = 0.5 (-2.3-3.3)

P > 0.05 NA Minimal 74 Paroxetine (20 mg) Desipramine (100 mg)

NM NA Total CL ↓78% Major CYP2D6

inhibition 3 PM NA Total CL ↓20% Moderate 73 Paroxetine (20 mg) Aripiprazole (3 mg)

CYP2D6*1/*1;*1/*5;*1/*10 (NM/IM) NA AUC ↑136% Substantial CYP2D6

inhibition 3

CYP2D6*5/*10;*10/*10;*10/*21 (IM) NA AUC ↑29% Moderate

75 Paroxetine (20 mg) R-methadone CYP2D6*1/*1 (NM) NA Css↑32% (P<0.05 vs before) Substantial CYP2D6 inhibition 2 CYP2D6*4/*4 (PM) NA Csss↑3% (P>0.05 vs before) Minimal

76 Quetiapine R-methadone CYP2D6*1/*1 (NM) No sign of over-medication was

observed.

CD ratio ↑30% Substantial CYP2D6 inhibition

2

CYP2D6*1/*4;*1/*3 (IM) CD ratio ↑21% Substantial

CYP2D6*3/*4;*4/*4 (PM) CD ratio ↑7% Minimal

77 Amiodarone (200 mg)

Flecainide (50 mg bid)

NM Amiodarone increased the

flecainide-induced QRS prolongation.

Metabolic CL ↓51% Major CYP2D6

inhibition 3 PM Metabolic CL ↓48% Major 80 Diphenhydramine (50 mg tid) Metoprolol (100 mg)

CYP2D6*1/*1;*1/*3;*1/*4;*1/*5 (NM/IM) Heart rate reduced significantly AUC ↑90% Substantial CYP2D6 inhibition

3

CYP2D6*4/*4;*4/*5 (PM) No significant influence on the heart

rate profile AUC ↓18% Minimal 78 Diphenhydramine (50 mg tid) Metoprolol (100 mg)

CYP2D6*1/*1;*1/*3;*1/*4;*1/*5 (NM/IM) NA Metabolic CL ↓61% Substantial CYP2D6

inhibition 3

CYP2D6*4/*4;*4/*5 (PM) NA Metabolic CL ↓14% Minimal

81 Diphenhydramine (50 mg tid)

Metoprolol (100 mg)

NM A significant effect on heart rate &

systolic blood pressure response

AUC ↑61% Substantial CYP2D6

inhibition 3

PM No significant effects AUC ↑10% Minimal

79 Dronedarone (800 mg)

Metoprolol (200 mg)

NM Dronedarone induces a dose-related

negative ionotropic effect only in NMs.

AUC ↑49% Moderate CYP2D6

inhibition 3 PM AUC ↑0.3% Minimal Dronedarone (1600 mg) Metoprolol (200 mg) NM AUC ↑115% Substantial PM AUC ↑7% Minimal 82 Amiodarone (1.2 g/day) Metoprolol (119 ± 51 mg)

inhibition 2

CYP2D6*1/*4;*2/*4 (IM) NA AUC ↑51% Moderate

83 Celecoxib (200 mg bid)

Metoprolol (50 mg)

CYP2D6*1/*1;*1/*2;*2/*2 (NM) NA AUC ↑103% Substantial CYP2D6

inhibition 3

(20)

6

70 Quinidine 50 mg qid R-flecainide (Low dose) NM a slight increase in

the pharmacodynamics effect (the mean of QRS & % arrhythmia suppression)

Metabolic CL ↓28% Substantial CYP2D6 inhibition 3 PM Metabolic CL ↑19% Minimal 71 Paroxetine (20 mg) Flecainide (200 mg)

inhibition

3

CYP2D6*1/*10 (NM) NA AUC ↑16% Moderate

CYP2D6*10/*10;*10/*30 (IM) NA AUC ↓2% Minimal

72 Paroxetine (20 mg)

Flecainide (200 mg)

CYP2D6*1/*1;*1/*2 (NM) Change in QTcF, msec = 6.5 (3.2-9.8)

P=0.002

NA Substantial CYP2D6

inhibition

3

CYP2D6*1/*10 (NM) Change in QTcF, msec = 6.7 (3.6-9.7)

P=0.001

NA Substantial

CYP2D6*10/*10;*10/*30 (IM) Change in QTcF, msec = 0.5 (-2.3-3.3)

P > 0.05 NA Minimal 74 Paroxetine (20 mg) Desipramine (100 mg)

NM NA Total CL ↓78% Major CYP2D6

inhibition 3 PM NA Total CL ↓20% Moderate 73 Paroxetine (20 mg) Aripiprazole (3 mg)

CYP2D6*1/*1;*1/*5;*1/*10 (NM/IM) NA AUC ↑136% Substantial CYP2D6

inhibition

3

CYP2D6*5/*10;*10/*10;*10/*21 (IM) NA AUC ↑29% Moderate

75 Paroxetine (20 mg) R-methadone CYP2D6*1/*1 (NM) NA Css↑32% (P<0.05 vs before) Substantial CYP2D6 inhibition 2 CYP2D6*4/*4 (PM) NA Csss↑3% (P>0.05 vs before) Minimal

76 Quetiapine R-methadone CYP2D6*1/*1 (NM) No sign of over-medication was

observed.

CD ratio ↑30% Substantial CYP2D6 inhibition

2

CYP2D6*1/*4;*1/*3 (IM) CD ratio ↑21% Substantial

CYP2D6*3/*4;*4/*4 (PM) CD ratio ↑7% Minimal

77 Amiodarone (200 mg)

Flecainide (50 mg bid)

NM Amiodarone increased the

flecainide-induced QRS prolongation.

Metabolic CL ↓51% Major CYP2D6

inhibition 3 PM Metabolic CL ↓48% Major 80 Diphenhydramine (50 mg tid) Metoprolol (100 mg)

CYP2D6*1/*1;*1/*3;*1/*4;*1/*5 (NM/IM) Heart rate reduced significantly AUC ↑90% Substantial CYP2D6 inhibition

3

CYP2D6*4/*4;*4/*5 (PM) No significant influence on the heart

rate profile AUC ↓18% Minimal 78 Diphenhydramine (50 mg tid) Metoprolol (100 mg)

CYP2D6*1/*1;*1/*3;*1/*4;*1/*5 (NM/IM) NA Metabolic CL ↓61% Substantial CYP2D6

inhibition

3

CYP2D6*4/*4;*4/*5 (PM) NA Metabolic CL ↓14% Minimal

81 Diphenhydramine (50 mg tid)

Metoprolol (100 mg)

NM A significant effect on heart rate &

systolic blood pressure response

AUC ↑61% Substantial CYP2D6

inhibition

3

PM No significant effects AUC ↑10% Minimal

79 Dronedarone (800 mg)

Metoprolol (200 mg)

NM Dronedarone induces a dose-related

negative ionotropic effect only in NMs.

inhibition 3 PM AUC ↑0.3% Minimal Dronedarone (1600 mg) Metoprolol (200 mg) NM AUC ↑115% Substantial PM AUC ↑7% Minimal 82 Amiodarone (1.2 g/day) Metoprolol (119 ± 51 mg)

inhibition

2

CYP2D6*1/*4;*2/*4 (IM) NA AUC ↑51% Moderate

83 Celecoxib (200 mg bid)

Metoprolol (50 mg)

CYP2D6*1/*1;*1/*2;*2/*2 (NM) NA AUC ↑103% Substantial CYP2D6

inhibition

3

(21)

6

84 Diphenhydramine (50 mg bid)

CYP2D6*1/*4;*1/*1 (NM/IM) NA Oral CL ↓59% Substantial CYP2D6

inhibition 3

CYP2D6*3/*4;*4/*4;*7/*7 (PM) NA Oral CL ↑13% Minimal

85 Thioridazine (40 mg)

S-Mianserin (30 mg)

CYP2D6*1/*1 (NM) NA Css ↑202% Major CYP2D6

inhibition 2

CYP2D6*1/*10 (NM) NA Css ↑80% Substantial

CYP2D6*1/*5 (IM) NA Css ↑102% Substantial

CYP2D6*5/*5 (PM) NA Css ↑34% Moderate

86 Propafenone (150 mg bid)

R-Mexiletine (100 mg bid)

inhibition 3

CYP2D6*4/*4;*4/*5 (PM) NA Oral CL ↓0% Minimal

S-Mexiletine (100 mg bid)

CYP2D6*1/*1;*1/*4 (NM/IM) NA Oral CL ↓33% Substantial

87 Fluoxetine (20 mg/day)

Risperidone (4 or 6 mg)

NM The severity & incidence of

extrapyramidal symptoms & adverse events did not significantly increase.

AUC ↑315% Major CYP2D6

inhibition 3 PM AUC ↑29% Moderate 88 Fluoxetine (20 mg) Tolterodine (2 mg bid)

CYP2D6*1/*1 (NM) NA AUC ↑1391% Major CYP2D6

inhibition 3

CYP2D6*1/*3 (IM) NA AUC ↑488% Major

CYP2D6*4/*4 (PM) NA AUC ↑24% Minimal

62 Quinidine (60 mg tid)

Propafenone (225 mg tid)

NM Maximum heart rate decreased by

10.7%

NA Major CYP2D6

inhibition 3

PM No incremental effect NA Minimal

63 Quinidine (50 mg)

Propafenone (450-900 mg)

NM Quinidinie did not influence

substantially electrocardiographic intervals & ventricular arrhythmia frequency in NM.

Oral CL ↓59% Major CYP2D6

inhibition 3

PM Oral CL ↑8 Minimal

89 CYP2D6 inhibitors (paroxetine,amiodarone, cimetidine, & ranitidine)

Tramadol (3 mg/kg)

CYP2D6*1/*1 (NM) NA (+)ODT AUC ↓93% Substantial CYP2D6

inhibition 2 CYP2D6*1/*3;*1/*4;*1/*5;*1/*6;*1/*10;*1/*41;*10/*41;*3/*41

;*4/*41;*6/*10;*6/*41 (NM/IM)

NA (+) ODT AUC ↓82% Substantial

CYP2D6*1/*4xN;*1/*41xN;*1/1*xN (UM) NA (+) ODT AUC ↓83% Substantial

90 Levomepromazine (5+5+5+10 mg) Codeine (60 mg qid) CYP2D6*1/*1 (NM) NA Median of o-demethylation ratio = 0.031 (0.009-0.042), P=0.0162 Substantial CYP2D6 inhibition 3

CYP2D6*1/*4 (IM) NA Ratio =0.026

(0.009-0.041), P>0.05 Minimal Interaction: Yes/Action: No 91 Imatinib (400 mg bid) Metoprolol (100 mg)

CYP2D6*1/*1;*1/*2 (NM) NA AUC ↑24% Moderate CYP2D6

inhibition 3

CYP2D6*1/*10 (NM) NA AUC ↑17% Minimal

92 Hydroxychloroquine (400 mg bid)

Metoprolol (100 mg)

CYP2D6*1/*1 (NM) NA AUC ↑51% Moderate CYP2D6

inhibition 3

CYP2D6*1/*4 (IM) NA AUC ↓3% Minimal

93 Pazopanib (800 mg) Dextromethorphan (30 mg) NM NA MR (10-24 h) = 0.16 (0.99-3.25), Ratio= 1.8 Moderate CYP2D6 inhibition 3 IM NA MR (10-24 h) = 0.39 (0.8-1.5), Ratio = 1.1 Minimal

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6

84 Diphenhydramine (50 mg bid)

inhibition

3

CYP2D6*3/*4;*4/*4;*7/*7 (PM) NA Oral CL ↑13% Minimal

85 Thioridazine (40 mg)

S-Mianserin (30 mg)

CYP2D6*1/*1 (NM) NA Css ↑202% Major CYP2D6

inhibition

2

CYP2D6*1/*10 (NM) NA Css ↑80% Substantial

CYP2D6*5/*5 (PM) NA Css ↑34% Moderate

86 Propafenone (150 mg bid)

R-Mexiletine (100 mg bid)

inhibition

3

S-Mexiletine (100 mg bid)

CYP2D6*1/*1;*1/*4 (NM/IM) NA Oral CL ↓33% Substantial

87 Fluoxetine (20 mg/day)

Risperidone (4 or 6 mg)

NM The severity & incidence of

extrapyramidal symptoms & adverse events did not significantly increase.

AUC ↑315% Major CYP2D6

inhibition 3 PM AUC ↑29% Moderate 88 Fluoxetine (20 mg) Tolterodine (2 mg bid)

CYP2D6*1/*1 (NM) NA AUC ↑1391% Major CYP2D6

inhibition

3

CYP2D6*1/*3 (IM) NA AUC ↑488% Major

CYP2D6*4/*4 (PM) NA AUC ↑24% Minimal

62 Quinidine (60 mg tid)

Propafenone (225 mg tid)

NM Maximum heart rate decreased by

10.7%

NA Major CYP2D6

inhibition

3

PM No incremental effect NA Minimal

63 Quinidine (50 mg)

Propafenone (450-900 mg)

NM Quinidinie did not influence

substantially electrocardiographic intervals & ventricular arrhythmia frequency in NM.

Oral CL ↓59% Major CYP2D6

inhibition

3

PM Oral CL ↑8 Minimal

89 CYP2D6 inhibitors (paroxetine,amiodarone, cimetidine, & ranitidine)

Tramadol (3 mg/kg)

CYP2D6*1/*1 (NM) NA (+)ODT AUC ↓93% Substantial CYP2D6

inhibition

2 CYP2D6*1/*3;*1/*4;*1/*5;*1/*6;*1/*10;*1/*41;*10/*41;*3/*41

;*4/*41;*6/*10;*6/*41 (NM/IM)

NA (+) ODT AUC ↓82% Substantial

CYP2D6*1/*4xN;*1/*41xN;*1/1*xN (UM) NA (+) ODT AUC ↓83% Substantial

90 Levomepromazine (5+5+5+10 mg) Codeine (60 mg qid) CYP2D6*1/*1 (NM) NA Median of o-demethylation ratio = 0.031 (0.009-0.042), P=0.0162 Substantial CYP2D6 inhibition 3

CYP2D6*1/*4 (IM) NA Ratio =0.026

(0.009-0.041), P>0.05 Minimal Interaction: Yes/Action: No 91 Imatinib (400 mg bid) Metoprolol (100 mg)

CYP2D6*1/*1;*1/*2 (NM) NA AUC ↑24% Moderate CYP2D6

inhibition

3

CYP2D6*1/*10 (NM) NA AUC ↑17% Minimal

92 Hydroxychloroquine (400 mg bid)

Metoprolol (100 mg)

CYP2D6*1/*1 (NM) NA AUC ↑51% Moderate CYP2D6

inhibition

3

CYP2D6*1/*4 (IM) NA AUC ↓3% Minimal

93 Pazopanib (800 mg) Dextromethorphan (30 mg) NM NA MR (10-24 h) = 0.16 (0.99-3.25), Ratio= 1.8 Moderate CYP2D6 inhibition 3 IM NA MR (10-24 h) = 0.39 (0.8-1.5), Ratio = 1.1 Minimal

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6

94 Methadone (20 to 50 mg) Dextromethorphan (30 mg) NM NA MR (0-8 h) = 0.02 (P < 0.05 vs. control). Ratio = 2 Moderate CYP2D6 inhibition 3 PM NA MR (0-8 h) = 5.83 (P > 0.05 vs. control). Ratio = 1.6 Minimal 95 Propafenone (225 mg tid) Lidocaine (2 mg/kg/hr) NM Propafenone-lidocaine combination

prolonged the PR (10%) & QRS (15%) intervals significantly

inhibition & decrease in liver blood flow

3

PM AUC ↓17% Minimal

AUC = Area under curve; INR = international normalized ratio; MR = metabolic ratio; ADP-Ag = Adenosine diphosphate-induced platelet aggregation; IPA = Inhibition of platelet aggregation; PT-INR = Prothrombin time expressed as international normalized ratio; CD ratio = concentration dose ratio; DMCLB = N-desmethyl-clobazam ; 4-OH-MP = 4-hydroxymephenytoin; CL = Clearance; bid = bis in die (twice a day); tid = ter in die (three times a day); NAPA = N-acetylprocainamide; QTcF = QT interval corrected using the Fridericia formula; Css = concentration of drug at steady-state; ODT = O-desmethyl tramadol; NA = Not available.

*If the genotype information was not available since genotyping was not performed, phenotype information was provided which was from phenotyping using probe substrates.

**The difference in pharmacokinetics values is counted in the same genotypic/phenotypic individuals using values before the administration of effector drug as reference. For example : the percentage in AUC difference in PM patients is formulated as follow : AUC diff in PM patients = (AUC after – AUC before)/AUC before x 100 %

AUC after = AUC value after administration of effector drug in the PM patient. AUC before = AUC value before administration of effector drug in the PM patient.

***The clinical impact of the interaction was estimated based on the criteria used by Verbeurgt et al and Polasek et al (supplementary 1)4,20

****The strength of evidence (0 to 4) was evaluated using the previously published criteria by van Roon et al. and Swen et al. (supplementary 1)11,24_.

#_{NM of CYP2D6 consisted of two normal function alleles i.e CYP2D6*1/*1; CYP2D6*1/*2; CYP2D6*2/*2 with metabolic activity score 2}

OR normal function allele combined with decreased function allele i.e. CYP2D6*1/*10; CYP2D6*1/*41; CYP2D6*2/*10; CYP2D6*2/*41 with metabolic activity score 1.5. IM of CYP2D6 consisted of one normal function allele combined with no function allele i.e. CYP2D6*1/*3; CYP2D6*1/*4; CYP2D6*1/*5; CYP2D6*1/*6; CYP2D6*1/*21; CYP2D6*2/*3; CYP2D6*2/*4; CYP2D6*2/*5 with metabolic activity score 1, OR two decreased function alleles i.e. CYP2D6*10/*41; CYP2D6*10/*10 with metabolic activity score 1 or one decreased function allele combined with no function allele i.e. CYP2D6*3/*41; CYP2D6*4/*41; CYP2D6*5/*10; CYP2D6*6/*10; CYP2D6*6/*41; CYP2D6*10/*21; CYP2D6*10/*30 with metabolic activity score 0.5. PM of CYP2D6 consisted of two no function alleles i.e. CYP2D6*3/*4; CYP2D6*4/*4; CYP2D6*4/*5; CYP2D6*4/*6; CYP2D6*5/*5; CYP2D6*5/*16; CYP2D6*7/*7 with metabolic activity score 0. UM of CYP2D6 consisted of two increased function alleles or more than two normal function alleles i.e. CYP2D6*1/*1xN; CYP2D6*1/*2xN; CYP2D6*1/*4xN; CYP2D6*1/*41xN; CYP2D6*2/*2xN with metabolic activity score >2.

both in NMs and PMs. This could be because amiodarone was not a CYP2D6-specific inhibitor and

might therefore, inhibit the other metabolic pathway of flecainide

77

_.

Other genetically determined DDIs were produced by metoprolol and some CYP2D6 inhibitors.

Diphenhydramine and dronedarone impaired metoprolol metabolism in NMs and IMs but not in

PMs

78-80

_{. Therefore, they only significantly affected heart rate profile and systolic blood pressure of}

metoprolol-treated NMs and IMs

79-81

_{. Additionally, amiodarone and celecoxib in their interactions}

with metoprolol indicated that NMs are more profoundly affected by the DDIs than IMs

82,83

_.

Furthermore, diphenhydramine and other CP2D6 inhibitors (thioridazine and propafenone) also

respectively obstructed venlafaxine, mianserin and mexiletine metabolism to a greater extent in

CYP2D6 with fully functional alleles than with reduced or dysfunctional alleles

84-86

_.

Second, the variability of pharmacokinetic values produced by CYP2D6 inhibition and

polymorphism did not cause different clinical activities because the substrate and its metabolite

had comparable clinical effects. The total concentration of active moiety compensated for

the pronounced kinetic differences, as presented by fluoxetine and risperidone or tolterodine

interactions

87,88

_{. Fluoxetine significantly inhibited risperidone metabolism in NMs and tolterodine}

metabolism both in NMs and IMs. The genetic polymorphism in PMs produced the same

metabolic inhibition with minimal effect of fluoxetine. Nevertheless, despite the increased plasma

concentration in NMs and PMs, the clinical effect seemed not to be influenced substantially. In

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