Pharmacogenetics of drug-drug

interactions
MUH. AKBAR BAHAR
CYP450 isoenzymes are subject to genetic polymorphism

PAINE, Mary F., et al. The human intestinal cytochrome P450"

pie". Drug metabolism and disposition, 2006.
Enzyme Genotype

CYP2D6
NM CYP2D6*1/*1; CYP2D6*1/*2; CYP2D6*2/*2; CYP2D6*1/*10; CYP2D6*1/*41; CYP2D6*2/*10; CYP2D6*2/*41

IM CYP2D6*1/*3; CYP2D6*1/*4; CYP2D6*1/*5; CYP2D6*1/*6; CYP2D6*1/*21; CYP2D6*2/*3; CYP2D6*2/*4; CYP2D6*2/*5;

CYP2D6*10/*41; CYP2D6*10/*10; CYP2D6*3/*41; CYP2D6*4/*41; CYP2D6*5/*10; CYP2D6*6/*10; CYP2D6*6/*41;
CYP2D6*10/*21; CYP2D6*10/*30
PM CYP2D6*3/*4; CYP2D6*4/*4; CYP2D6*4/*5; CYP2D6*4/*6; CYP2D6*5/*5; CYP2D6*5/*16; CYP2D6*7/*7

UM CYP2D6*1/*1xN; CYP2D6*1/*2xN; CYP2D6*1/*4xN; CYP2D6*1/*41xN; CYP2D6*2/*2xN.

CYP2C19
NM CYP2C19*1/*1

IM CYP2C19*1/*2; CYP2C19*1/*3

PM CYP2C19*2/*2; CYP2C19*2/*3; CYP2C19*3/*3

RM CYP2C19*1/*17

UM CYP2C19*17/*17

CYP2C9
NM CYP2C9*1/*1

IM CYP2C9*1/*2; CYP2C9*1/*3

PM CYP2C9*2/*2; CYP2C9*2/*3; CYP2C9*3/*3

Substrate

Subject to genetic
polymorphisms!

Inducer/inhibitor
Transporter

Same effects?
Same managements?
Phenoconversion
• Phenoconversion  genotype-phenotype mismatch due to non-
genetic extrinsic factors (drugs, diseases).

• For example: a phenomenon that converts genotypic EM/IM/UM to

phenotypic PM of drugs, thereby modifying their clinical response to
that of genotypic PMs.

• CYP enzymes with a reduction-of-function allele are more prone to

undergo a phenoconversion with a co-presence of a CYP modulator
(inhibitor/inducer) than those with active alleles.
Category Description
Major > 200% increase in AUC predicted; clearance decreases > 67%
> 90% reduction in AUC predicted; clearance increases ≥ 900%
Contraindicated interaction

Substantial 75-200% increase in AUC predicted; clearance decreases ≥ 43% to < 67%
60-90% reduction in AUC predicted; clearance increases ≥ 150% to < 900%
Need a monitoring or dose adjustment

Moderate 25-75% increase in AUC predicted; clearance decreases ≥ 20% to < 43%
25-60% reduction in AUC predicted; clearance increases ≥ 33 % to < 150%
Possible interaction

Minimal <25% change in AUC predicted; clearance decreases < 20% or increases < 33 %
No clinically significant interactions

1. Verbeurgt P, Mamiya T, Oesterheld J: How common are drug and gene interactions? Prevalence in a sample of 1143 patients with CYP2C9, CYP2C19 and
CYP2D6 genotyping. Pharmacogenomics 15(5), 655-665 (2014).
2. Polasek TM, Lin FP, Miners JO, Doogue MP: Perpetrators of pharmacokinetic drug-drug interactions arising from altered cytochrome P450 activity: a criteria-
based assessment. Br. J. Clin. Pharmacol. 71(5), 727-736 (2011).
The area under the plasma drug
concentration-time curve (AUC)
reflects the actual body exposure to
drug after administration of a dose
of the drug and is expressed in
mg*h/L
43.7-48.5/48.5*100 = -10%

54.6-23.1/23.1*100 = 141%
1514-940/940*100 = 4354-3956/3956*100 =
Stockley
Example A
A patient is treated with amiodaron and is prescribed phenytoin. Phenytoin is a substrate for CYP2C9, amiodaron inhibits
CYP2C9. Advice guideline: replace amiodaron by another antiarrhytmic drug.
If the patient is a PM for CYP2C9 the switch is unnecessary.

Example B
A patient is treated with metoprolol and then paroxetine is prescribed (metoprolol is metabolized by CYP2D6,
paroxetine inhibits CYP2D6). Advice guideline: preferably do not use this combination and replace paroxetine by a SSRI
not inhibiting CYP2D6.
If the patient is a PM for CYP2D6 this restriction in drug use is unnecessary.
Key points
• Genetic predisposition has a pronounced role in determining the magnitude of drug–drug
interactions (DDIs).

• DDIs occur in a genotype-dependent manner.

• The scenario of DDI is highly dependent on the properties of perpetrator and object drugs, and
the type and function of the enzymes affected.

• The impact of the addition of an effector drug to the context of a DDI is greatest in normal
metabolizer (NM), less in intermediate metabolizer (IM) and least in poor metabolizer (PM).
Polymorphism has an impact in the reverse order.

• Generalization in drug interaction management can lead to inappropriate administration