Current molecular tools lack the ability to differentiate the activity of CYP3A4 and CYP3A5 in biological samples such as human liver microsomes. Kinetic experiments and the CYP3A4 crystal structure indicate that the active sites of both enzymes are large and flexible, and have more than one binding subsite within the active site. 1-(4-Imidazopyridinyl-7phenyl)-3-(4'-cyanobiphenyl) urea (SR-918...

PURPOSE Despite the advances in the pharmacological treatment of epilepsy, pharmacoresistance still remains challenging. Understanding of the pharmacogenetic causes is critical to predict drug response hence providing a basis for personalized medications. Genetic alteration in activity of drug target and drug metabolizing proteins could explain the development of pharmacoresistant epilepsy. So ...

The purpose of this study was to compare the kinetics of intestinal and hepatic cytochrome P-450 3A (CYP3A) inhibition by using microsomal midazolam 1'-hydroxylation as a marker of enzyme activity. The effect of two antifungal agents commonly implicated in CYP3A drug-drug interactions was examined. Inhibition type and affinities were determined for human liver and intestinal microsomes screened...

Acetaminophen is a leading cause of acute liver failure (ALF). Genetic differences might predispose some individuals to develop ALF. In this exploratory study, we evaluated genotype frequency differences among patients enrolled by the ALF Study Group who had developed ALF either intentionally from a singletime-point overdose of acetaminophen (n = 78), unintentionally after chronic high doses of...

Cynomolgus and rhesus macaques are frequently used in preclinical trials due to their close evolutionary relationships to humans. We conducted an initial screening for genetic variants in cynomolgus and rhesus macaque genes orthologous to human CYP3A4 and CYP3A5. Genetic screening of 78 Indochinese and Indonesian cynomolgus macaques and 34 Chinese rhesus macaques revealed a combined total of 42...

Acetaminophen is a leading cause of acute liver failure (ALF). Genetic differences might predispose some individuals to develop ALF. In this exploratory study, we evaluated genotype frequency differences among patients enrolled by the ALF Study Group who had developed ALF either intentionally from a singletime-point overdose of acetaminophen (n = 78), unintentionally after chronic high doses of...

Pesticide exposure is associated with various neoplastic diseases and congenital malformations. Animal studies also indicated that pesticides may be metabolized by cytochrome P450 3A5 (CYP3A5) enzymes, paraoxonases (PON1 and PON2), or glutathione S-transferases (GSTM1, GSTT1, and GSTP1). However, little is known about the genotoxicity of pesticides in people with various genetic polymorphisms o...

The human CYP3A subfamily plays a dominant role in the metabolic elimination of more drugs than any other biotransformation enzyme. CYP3A enzyme is localized in the liver and small intestine and thus contributes to first-pass and systemic metabolism. CYP3A expression varies as much as 40-fold in liver and small intestine donor tissues. CYP3A-dependent in vivo drug clearance appears to be unimod...

A recent publication by Lu et al. (2014) described the effects of the CYP3A5 genotype on Selzentry/Celsentri (maraviroc) concentrations. Maraviroc is a chemokine (C-C motif) receptor 5 inhibitor approved for the treatment of human immunodeficiency virus (HIV) infection (Dorr et al., 2005). Maraviroc pharmacokinetics in subjects who were heterozygous (n = 8; one CYP3A5*1 and one dysfunctional al...

PURPOSE To evaluate the effect of naturally occurring variants in genes encoding the cytochrome P450 (CYP) isoforms CYP3A4 and CYP3A5 in patients with cancer receiving midazolam as a phenotyping probe. EXPERIMENTAL DESIGN Five variants in CYP3A4 and CYP3A5 were evaluated in 58 patients (21 women and 37 men) receiving a short i.v. bolus of midazolam (dose, 0.0145 or 0.025 mg/kg). Midazolam con...