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Abstract: Harmaline is a β-carboline alkaloid showing neuroprotective and neurotoxic properties. Our recent studies have revealed an important role for cytochrome P450 2D6 (CYP2D6) in harmaline O-demethylation. This study, therefore, aimed to delineate the effects of CYP2D6 phenotype/genotype on harmaline metabolism, pharmacokinetics (PK) and pharmacodynamics (PD), and to develop a pharmacogenetics mechanism-based compartmental PK model. In vitro kinetic studies on metabolite formation in human CYP2D6 extensive metabolizer (EM) and poor metabolizer (PM) hepatocytes indicated that harmaline O-demethylase activity (V max/K m) was about 9-fold higher in EM hepatocytes. Substrate depletion showed mono-exponential decay trait, and estimated in vitro harmaline clearance (CLint, μL/min/106 cells) was significantly lower in PM hepatocytes (28.5) than EM hepatocytes (71.1). In vivo studies in CYP2D6-humanized and wild-type mouse models showed that wild-type mice were subjected to higher and longer exposure to harmaline (5 and 15mg/kg; i.v. and i.p.), and more severe hypothermic responses. The PK/PD data were nicely described by our pharmacogenetics-based PK model involving the clearance of drug by CYP2D6 (CLCYP2D6) and other mechanisms (CLother), and an indirect response PD model, respectively. Wild-type mice were also more sensitive to harmaline in marble-burying tests, as manifested by significantly lower ED50 and steeper Hill slope. These findings suggest that distinct CYP2D6 status may cause considerable variations in harmaline metabolism, PK and PD. In addition, the pharmacogenetics-based PK model may be extended to define PK difference caused by other polymorphic drug-metabolizing enzyme in different populations. [Copyright &y& Elsevier]

Determining the in vivo significance of a specific enzyme, transporter, or xenobiotic receptor in drug metabolism and pharmacokinetics may be hampered by gene multiplicity and complexity, levels of expression, and interaction between various components involved. The development of knockout (loss-of-function) and transgenic (gain-of-function) mouse models opens the door to the improved understanding of gene function in a whole-body system. There is also growing interest in the development of humanized mice to overcome species differences in drug metabolism and disposition. This review, therefore, aims to summarize and discuss some successful examples of drug-metabolizing enzyme, transporter, and nuclear-receptor genetically modified mouse models. These genetically modified mouse models have been proven as invaluable models for understanding in vivo function of drug-metabolizing enzymes, transporters, and xenobiotic receptors in drug metabolism and transport, as well as predicting potential drug-drug interaction and toxicity in humans. Nevertheless, concerns remain about interpretation of data obtained from such genetically modified mouse models, in which the expression of related genes is altered significantly. [ABSTRACT FROM AUTHOR]