Effects of CYP2D6 status on harmaline metabolism, pharmacokinetics and pharmacodynamics, and a pharmacogenetics-based pharmacokinetic model

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 Odemethylation. 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 (CL int , μL/min/10 6 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 15 mg/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 (CL CYP2D6 ) and other mechanisms (CL other ), 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 ED 50 and steeper Hill slope. These findings suggest that distinct CYP2D6 status may cause considerable variations in harmaline metabolism, PK and PD. In addition, the pharmacogeneticsbased PK model may be extended to define PK difference caused by other polymorphic drugmetabolizing enzyme in different populations.

Pharmacokinetic Interactions between Monoamine Oxidase A Inhibitor Harmaline and 5-Methoxy-N,N-Dimethyltryptamine, and the Impact of CYP2D6 Status

“…and i.p. administration of harmaline (5 or 15 mg/kg) alone (Wu et al, 2009). In this study, 0.2-0.3 ml of blood sample was collected from one mouse at various time points (15-255 minutes, n = 4 per time point), and each mouse was sampled once.…”

“…In our previous single-dose PK studies, two-compartmental models with first-order absorption and linear or capacity-limited elimination from the central compartments have been established to describe the PK properties of harmaline and 5-MeO-DMT, respectively (Wu et al, 2009;Shen et al, 2011b). These models were adopted into this study with modifications to characterize the PK profiles of harmaline and 5-MeO-DMT under the DDI condition.…”

“…All PK parameters for harmaline were obtained from our previous analysis (Wu et al, 2009), except that bioavailability (F H ) of the 2 mg/kg dose level of harmaline was estimated in the present study. k a-H (0.307 1/min) is the absorption rate constant, and V C-H (2.43 l/kg), and V P-H (2.86 l/kg) are the volume of central and peripheral compartments, respectively.…”

“…and i.p. administration (Wu et al, 2009). In this study, serum harmaline concentrations were also monitored over time after coadministration of harmaline and 5-MeO-DMT (Figs.…”

“…Furthermore, the blockage of MAO-A-controlled deamination metabolism may result in an enhanced O-demethylation of 5-MeO-DMT (Shen et al, 2010b), which is catalyzed by polymorphic CYP2D6 (Zanger et al, 2004) to generate bufotenine (Yu et al, 2003a), an active metabolite with 10-fold higher affinity to the 5-HT 2A receptor than 5-MeO-DMT (Roth et al, 1997). In addition, the PK of harmaline is affected by CYP2D6 status, as demonstrated by a faster systemic clearance in CYP2D6-humanized (Tg-CYP2D6) mice than that in wild-type mice (Yu et al, 2003b;Wu et al, 2009). Therefore, concurrent harmaline may interact agonistically with 5-MeO-DMT at both pharmacodynamic and PK levels (Shen et al, 2010a), and CYP2D6 genetic polymorphism may further complicate their PK interactions.…”