Accumulated evidence suggests that cross-talk between the pregnane X receptor (PXR) and the constitutive androstane receptor (CAR) results in shared transcriptional activation of CYP2B and CYP3A genes. Although most data imply symmetrical cross-regulation of these genes by rodent PXR and CAR, the actual selectivities of the corresponding human receptors are unknown. The objective of this study ...

Some inhibitory agents against CYP2B6 have been reported, but none of these has been extensively characterized or compared with others, as to the potency and selectivity of inhibition toward CYP2B6. The goal of this work was to find a selective and potent chemical in vitro inhibitor toward CYP2B6 using bupropion hydroxylation as a model reaction. At the initial screening of more than 30 substan...

There is considerable evidence that pregnancy changes the disposition of drugs in an enzymeand gestational stage–specific manner. On the basis of probe drug studies, the activity of CYP3A4 and CYP2D6 increases and CYP1A2 decreases during human pregnancy. However, no studies of CYP2B6 activity during human pregnancy have been conducted. In rodent models and in HepG2 cells, CYP2B enzymes have bee...

There is considerable evidence that pregnancy changes the disposition of drugs in an enzymeand gestational stage–specific manner. On the basis of probe drug studies, the activity of CYP3A4 and CYP2D6 increases and CYP1A2 decreases during human pregnancy. However, no studies of CYP2B6 activity during human pregnancy have been conducted. In rodent models and in HepG2 cells, CYP2B enzymes have bee...

Methadone is a μ-opioid receptor agonist widely used in the treatment of narcotic addiction and chronic pain conditions. Methadone is metabolized predominantly in the liver by cytochromes P450 to its pharmacologically inactive primary metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine. Initial in vitro data suggested that CYP3A4 is the major isoform responsible for the in vivo clearan...

The long-acting opioid methadone displays considerable unexplained interindividual pharmacokinetic variability. Methadone metabolism clinically occurs primarily by N-demethylation to 2-ethyl-1,5-dimethyl3,3-diphenylpyrrolidine (EDDP), catalyzed predominantly by CYP2B6. Retrospective studies suggest that the common allele variant CYP2B6*6 may influence methadone plasma concentrations. The cataly...

We have investigated the mechanisms by which clopidogrel inactivates human cytochrome P450 2B6 (CYP2B6) in a reconstituted system. It was found that clopidogrel and its thiolactone metabolite, 2-oxo-clopidogrel, both inactivate CYP2B6 in a time- and concentration-dependent manner. On the basis of k(inact)/K(I) ratios, clopidogrel is approximately 5 times more efficient than 2-oxo-clopidogrel in...

CYP2B6 is a highly inducible and polymorphic enzyme involved in the metabolism of an increasing number of clinically important drugs. Significant interindividual variability in CYP2B6 expression has been attributed to either genetic polymorphisms or chemical-mediated induction through the activation of constitutive androstane receptor and/or pregnane X receptor (PXR). It was reported that the -...

There is considerable evidence that pregnancy changes the disposition of drugs in an enzymeand gestational stage–specific manner. On the basis of probe drug studies, the activity of CYP3A4 and CYP2D6 increases and CYP1A2 decreases during human pregnancy. However, no studies of CYP2B6 activity during human pregnancy have been conducted. In rodent models and in HepG2 cells, CYP2B enzymes have bee...

There is considerable evidence that pregnancy changes the disposition of drugs in an enzymeand gestational stage–specific manner. On the basis of probe drug studies, the activity of CYP3A4 and CYP2D6 increases and CYP1A2 decreases during human pregnancy. However, no studies of CYP2B6 activity during human pregnancy have been conducted. In rodent models and in HepG2 cells, CYP2B enzymes have bee...