Metabolism of Zaleplon by human hepatic microsomal cytochrome P450 isoforms

Abstract

1. The metabolism of Zaleplon (CL-284,846; ZAL) has been studied in human liver microsomal preparations and in cDNA-expressed human cytochrome P450 (CYP) isoforms. 2. Human liver microsomes catalysed the NADPH-dependent N-deethylation of ZAL to DZAL (CL-284,859), but not to two other known in vivo metabolites, namely M1 (CL-345,644) and M2 (CL-345,905). Sigmoidal kinetic plots were observed for ZAL deethylation indicating positive cooperativity. 3. The metabolism of ZAL to DZAL was determined in a characterized bank of 24 human liver microsomal preparations. Good correlations (r2 = 0.734-0.937) were observed with caffeine 8-hydroxylase, diazepam 3-hydroxylase, dextromethorphan N-demethylase and testosterone 2 beta-, 6 beta- and 15 beta-hydroxylase activities, which are all catalysed by CYP3A isoforms. In contrast, poor correlations (r2 = 0.152-0.428) were observed for enzymatic markers for CYP1A2, CYP2A6, CYP2C9/10, CYP2D6, CYP2E1 and CYP4A9/11. 4. The metabolism of ZAL to DZAL in human liver microsomes was inhibited to 6-15% of control by 5-50 microM of the mechanism-based CYP3A inhibitor troleandomycin. Whereas some inhibition of DZAL formation was observed in the presence of 200 microM diethyldithiocarbamate, 5-50 microM furafylline, 2-20 microM sulphaphenazole, 50-500 microM S-mephenytoin and 1-10 microM quinidine had little effect. 5. Using human B-lymphoblastoid cell microsomes containing cDNA-expressed CYP isoforms, ZAL was metabolized to DZAL by CYP3A4, hut not to any great extent by CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP2E1. 6. In contrast with ZAL, the NADPH-dependent N-deethylation of M2 to M1 proceeded at only a very low rate with both human liver microsomes and cDNA-expressed CYP3A4. 7. In summary, by correlation analysis, chemical inhibition studies and the use of cDNA-expressed CYPs, ZAL N-deethylation to DZAL in human liver appears to be catalysed by CYP3A isoforms.

Zaleplon pharmacokinetics and absolute bioavailability

“…Zaleplon is primarily metabolized by aldehyde oxidase to form 5-oxo-zaleplon, and secondarily by CYP3A4 to form desethylzaleplon, which is quickly converted by aldehyde oxidase to form 5-oxodesethylzaleplon [8]. These oxidative metabolites were further metabolized by conjugation and subsequently eliminated in urine.…”

Toxicology of Specific Substances

“…Zaleplon (Fig. 51.35) is extensively metabolised also via CYP3A4 to inactive metabolites, mainly via oxidation to 5-oxo-zaleplon with less than 1% of dose excreted unchanged in urine (Renwick et al 1998). Zopiclone (Fig.…”

Mechanisms of Pharmacokinetic and Pharmacodynamic Drug Interactions Associated with Ritonavir‐Enhanced Tipranavir

“…Zaleplon, a pyrazolopyrimidine used to treat short-term insomnia, 122 is primarily metabolized by aldehyde oxidase with only a minor contribution by CYP3A. [123][124][125] Therefore, tipranavirritonavir is not expected to significantly influence zaleplon pharmacokinetics.…”