Metabolism Based Drus Interactions

Abstract

One of the main types of drug-drug interaction (DDI) is pharmacokinetic DDI, in which one drug alters the pharmacokinetics of another drug. Here, we discuss about the two main modes of pharmacokinetic DDIs:

1. Drug metabolizing enzyme inhibition

(a) Reversible

(b) Time-dependent (quasi-reversible and irreversible)

2. Enzyme induction

The most understood and studied DDI is the metabolism-based type. Here, we discuss inhibition, induction, and reaction pheno-typing in an in vitro setting. We also discuss in vivo drug-drug interaction predictions based on in vitro data. Useful tables of probe substrates, selective inhibitors, and inducers are included.

Contents

5.1 List of Abbreviations 73

5.2 Basic Concepts and Definitions 74

5.3 Enzyme Kinetics in the Absence of an Inhibitor 75

5.4 In Vitro Enzyme Inhibition 78

5.5 Enzyme Induction 84

5.6 Reaction Phenotyping 86

5.7 Predicting In Vivo Drug Interactions 88

References 94

Further Readings 94

5.1 LIST OF ABBREVIATIONS

AhR Aryl hydrocarbon receptor ALDH Aldehyde dehydrogenase

S.C. Khojasteh et al., Drug Metabolism and Pharmacokinetics 73

Quick Guide, DOI 10.1007/978-1-4419-5629-3_5, © Springer Science+Business Media, LLC 2011

AUC Area under the curve

AUCj Area under the curve in the presence of an inhibitor

CAR Constitutive androstsane receptor

Cmax Maximum plasma concentration

CLint Intrinsic clearance

DME Drug metabolizing enzyme

E Enzyme fm Fraction metabolized by an enzyme

GST Glutathione transferase k Rate constant kcat First-order rate constant for the formation of product kinact First-order rate constant for the formation of inactivated enzyme

Km Michaelis-Menten constant (i.e., [S] at Vmax/2)

K Inhibitory constant (competitive, Nerversible)

KI Concentration of inactivator (or inhibitor) at Imax/2 (irreversible)

I Inhibitor

Imax Maximal rate of inactivation

IC50 Half maximal inhibitory concentration (i.e., [I] when

MBI Mechanism-based inhibition po Oral dosing

S Substrate

ES Enzyme-substrate complex

P Product

P450 Cytochrome P450

PXR Pregnane X receptor

SULT Sulfotransferase

TDI Time-dependent inhibition

UGT Uridine diphosphate glucuronosyltransferase v Reaction velocity vi Reaction velocity in the presence of an inhibitor Vmax Maximal velocity at saturated substrate concentration

Was this article helpful?

0 0

Post a comment