Minipig as a model for drug metabolism in man: Comparison of in vitro and in vivo metabolism of propafenone

Eva Anzenbacherová,František Perlík,Jana Zoulová,Jiřina Martínková,Jaroslav Květina,Jitka Ulrichová,Pavel Anzenbacher,Zbyněk Svoboda

doi:10.5507/bp.2003.021

Abstract

To prove the suitability of minipigs as experimental animal in modeling of the drug metabolism and pharmacokine-tics in man, propafenone metabolism in vitro at the microsomal level as well as propafenone pharmacokinetics in the minipig was studied. The results were compared with those obtained for humans. It can be concluded that whereas the microsomal in vitro system of minipig may be a good model for drug metabolism in the man, the pharmacokinetics in the whole organism is more complex reflecting differences in substrate specificities of many enzymatic and transport systems. In this particular case, it has been documented that the glucuronidation of propafenone principal metabolite (5-hydroxypropafenone) is more efficient in the minipig.

Highlights

The search for an ideal or almost ideal experimental model of drug pharmacokinetics in man continues as the rat and more generally rodent models were shown not to correspond well to the metabolic properties of human liver monooxygenases[1, 2]
The importance of a proper model of drug metabolism by cytochromes P450 is given by the fact that the majority of drugs undergoing biotransformation is metabolized by these enzymes which are known to take part in many different reactions involving exogenous as well as endogenous substrates as e.g. prostaglandins or steroids[3]
Minipigs are considered as experimental model in pharmacology for their apparent physiological as well as metabolic similarities to the man

Summary

INTRODUCTION

The search for an ideal or almost ideal experimental model of drug pharmacokinetics in man continues as the rat and more generally rodent models were shown not to correspond well to the metabolic properties of human liver monooxygenases[1, 2] Metabolism of several compounds by minipig liver microsomes has been studied[4,5,6,7] and properties of individual isolated liver cytochromes were described[8] indicating that minipig-derived systems at the subcellular (microsomal) or molecular level can mimic these of the human origin. A study on pharmacokinetics of two model drugs, atenolol and 5-aminosalicylic acid (5-ASA) as drugs undergoing small (atenolol) and extensive (5-ASA) first pass metabolism in liver, indicated that the minipig may give reasonable estimates of pharmacokinetic parameters comparable to these obtained in human[9]. Involvement of enzymes of the second phase of drug biotransformation, namely, UDP-glucuronosyltransferases, has been documented in propafenone metabolism in the man[11]

MATERIALS AND METHODS

Methods

RESULTS AND DISCUSSION