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CYP Induction-Mediated Drug Interactions: in Vitro Assessment and Clinical Implications

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Abstract

Cytochrome P450 (CYP) induction-mediated interaction is one of the major concerns in clinical practice and for the pharmaceutical industry. There are two major issues associated with CYP induction: a reduction in therapeutic efficacy of comedications and an induction in reactive metabolite-induced toxicity. Because CYP induction is a metabolic liability in drug therapy, it is highly desirable to develop new drug candidates that are not potent CYP inducer to avoid the potential of CYP induction-mediated drug interactions. For this reason, today, many drug companies routinely include the assessment of CYP induction at the stage of drug discovery as part of the selection processes of new drug candidates for further clinical development. The purpose of this article is to review the molecular mechanisms of CYP induction and the clinical implications, including pharmacokinetic and pharmacodynamic consequences. In addition, factors that affect the degree of CYP induction and extrapolation of in vitro CYP induction data to in vivo situations will also be discussed. Finally, assessment of the potential of CYP induction at the drug discovery and development stage will be discussed.

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Abbreviations

AF-2:

activation factor 2

AhR:

aryl hydrocarbon receptor

Arnt:

AhR nuclear translocator

AUCiv :

area under plasma concentration–time curve after intravenous dosing

AUCpo :

area under plasma concentration–time curve after oral dosing

CaMK:

calcium/cAMP-dependent kinase

CAR:

constitutive androstane receptor

CCRP:

cytoplasmic CAR retention protein

C max :

maximal plasma concentration following oral dose

CYP:

cytochrome P450

DNA:

deoxyribonucleic acid

DBD:

DNA binding domain

DMSO:

dimethylsulfoxide

DR:

direct repeat

EC50 :

effective concentration for 50% maximal CYP induction

ER:

everted repeat

EM:

extensive metabolizer

E max :

maximal CYP induction

GR:

glucocorticoid receptor

GSH:

glutathione

HIV:

human immunodeficiency virus

Hsp90:

heat shock protein 90

INR:

international normalized ratio

IR:

inverted repeat

LBD:

ligand binding domain

mRNA:

messenger ribonucleic acid

NAPQI:

N-acetyl-p-benzoquinone imine

NF1:

nuclear factor 1

PAS:

Per-Arnt-Sim

PB:

phenobarbital

PBREM:

PB-responsive enhancer module

PCN:

pregnenolone-16α-carbonite

PhIP:

2-amino-1-methyl-6-phenyl-imidazole[4,5-b]pyridine

PM:

poor metabolizer

PXR:

pregnane X receptor

RARE:

retinoid acid response element

RXR:

retinoid X receptor

SNP:

single nucleotide polymorphism

SRC-1:

steroid receptor cofactor-1

TCDD:

2,3,7,8-tetraxchlorodibenzo-p-dioxin

TCPOBOP:

(1,4-bis-[2-(3,5,-dichloropyridyloxy)]benzene)

UGT:

UDP-glucuronosyltransferase

XRE:

xenobiotic-responsive element

XREM:

xenobiotic-responsive enhancer module

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    Jiunn H. Lin

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Lin, J.H. CYP Induction-Mediated Drug Interactions: in Vitro Assessment and Clinical Implications. Pharm Res 23, 1089–1116 (2006). https://doi.org/10.1007/s11095-006-0277-7

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