Effects of enzyme inducers and inhibitor on the pharmacokinetics of intravenous 2-(allylthio)pyrazine, a new chemoprotective agent, in rats.

In order to find what types of hepatic cytochrome P450 (CYP) isozymes are involved in the metabolism of 2-(allylthio)pyrazine (2-AP) in rats, enzyme inducers, such as phenobarbital, 3-methylcholanthrene, dexamethasone, or isoniazid, and an enzyme inhibitor, such as SKF 525-A were pretreated. After 1-min intravenous administration of 2-AP, 50 mg/kg, to rats pretreated with SKF 525-A (a non-specific CYP inhibitor in rats), the plasma concentrations were significantly higher, and the area under plasma concentration-time curve from time zero to time infinity (AUC) was significantly greater (1365 compared with 1034 microg min/mL) as a result of significantly slower total body clearance (Cl) (36.6 compared with 48.3 mL/min/kg) than those in control rats, indicating that 2-AP was metabolized by CYP isozymes. After 1-min intravenous administration of 2-AP, 50 mg/kg, to rats pretreated with dexamethasone (an inducer of CYP3A in rats), phenobarbital (an inducer of CYP2B1/2, 2C6, 2C7, and 3A1/2 in rats), and 3-methylcholanthrene (an inducer of CYP1A1/2 and 2A1 in rats), the plasma concentrations were significantly lower, and AUC was significantly smaller (27, 41 and 60% decrease, respectively, compared with respective control rats) owing to faster Cl [37 (p>0.05), 70 (p<0.001), and 150% (p<0.001) increase, respectively, compared with respective control rats].