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The objective of this study was to compare the pharmacokinetics and metabolism of zaleplon (ZAL) in rats under hypoxic and normoxic condition and the effect of hypoxia on the protein expression and activities of the main metabolic enzyme CYP3A1/2. The LC-MS/MS method was successfully used for the determination of ZAL in rat plasma after an oral administration under normoxic and hypoxic exposure. The expressions of CYP3A1/2 proteins were determined by the Western blotting method. The activity of CYP3A1/2 in rat liver microsomes was determined by the LC-MS/MS method using testosterone as the probe drug. The metabolites of ZAL in rats were identified by LC-MSn by comparison of their ESI-MSn spectra and chromatographic retention times to those of the parent drug between the normoxic and the hypoxic group. The results indicated that the values of AUC and Cmax were significantly higher in the hypoxia exposure for 3 d (H3) group than that in the normoxic group, and the Vd and CL were markedly lower in the H3 group than those in the normoxic group. Hypoxia could markedly inhibit the protein expression and activities of CYP3A1/2, resulting in reduction of the metabolic rate of the drug and enhancement of the systematic exposure. Our data indicated that the expression and activity of CYP3A1/2 mainly affected the drug metabolism and pharmacokinetic characteristics of ZAL under the hypoxic condition.

Effect of hypoxia on the pharmacokinetics and metabolism of zaleplon as a probe of CYP3A1/2 activity