In Vivo Assessment of Cytochrome P450 3A4 and P-Glycoprotein Activity:Impact on Clinical Practice

Wim Lemahieu; Bart Maes

Abstract

Both bioavailability and clearance of most drugs for human use are strongly determined by hepatic and intestinal metabolism and transport. This is especially relevant for so-called narrow therapeutic index drugs, necessitating the use of therapeutic drug monitoring in many clinical settings. Cytochrome P450 3A4 (CYP3A4) is a key enzyme involved in over half of all phase I drug metabolism reactions and is abundantly present in the endoplasmic reticulum of both hepatocytes and enterocytes. P-glycoprotein (PGP), also known as MDR1 or ABCB1, is one of the first discovered and still most important active drug efflux pumps. Its localization on the apical cell membrane of hepatocytes zooming bile canaliculi and its relative distribution along the intestinal tract (PGP is mainly situated in the distal gastrointestinal tract, as opposed to CYP3A4, which is most prevalent in the proximal part) strongly suggests an interplay between these two proteins, optimizing the organisms defence against xenobiotics. To date, the main part of all research on CYP3A4 and PGP has been conducted in vitro and mostly using systems expressing either CYP3A4 or PGP. Since it has proven difficult to ‘scale up’ from in vitro results to clinically relevant phenomena such as potentially life threatening drug-drug interactions, several attempts have been made to bridge this ‘gap’ by assessing CYP3A4 and PGP activity in vivo. This review will focus on currently available methods for CYP3A4/PGP measurement in vivo and its impact on clinical practice, particularly in the field of clinical immunosuppression.

Keywords: CYP3A4 substrates, Drug Efflux Transporter, Dextromethorphan, Cortisol, benzodiazepines, Cyclosporin A, Tacrolimus

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