Title
Inhibition of zaleplon metabolism by cimetidine in the human liver: In vitro studies with subcellular fractions and precision-cut liver slices
Author
Renwick, A.B.
Ball, S.E.
Tredger, J.M.
Price, R.J.
Walters, D.G.
Kao, J.
Scatina, J.A.
Lake, B.G.
TNO Voeding
Publication year
2002
Abstract
The effect of cimetidine on the metabolism of zaleplon (ZAL) in human liver subcellular fractions and precision-cut liver slices was investigated. 2. ZAL was metabolized to a number of products including 5-oxo-ZAL (M2), which is known to be formed by aldehyde oxidase, N-desethyl-ZAL (DZAL), which is known to be formed by CYP3A forms, and N-desethyl-5-oxo-ZAL (M1). 3. Human liver microsomes catalysed the NADPH-dependent metabolism of ZAL to DZAL. Kinetic analysis of three microsomal preparations revealed mean (±SEM) S50 and Vmax of 310±24 μM and 920±274 pmol/min/mg protein, respectively. 4. Human liver cytosol preparations catalysed the metabolism of ZAL to M2. Kinetic analysis of three cytosol preparations revealed mean (±SEM), Km and Vmax of 124±14 μM and 564±143 pmol/min/mg protein, respectively. 5. Cimetidine inhibited ZAL metabolism to DZAL in liver microsomes and to M2 in the liver cytosol. With a ZAL substrate concentration of 62 μM, the calculated mean (±SEM, n=3) IC50 were 596±103 and 231±23 μM for DZAL and M2 formation, respectively. Kinetic analysis revealed that cimetidine was a competitive inhibitor of M2 formation in liver cytosol with a mean (±SEM, n=3) Ki of 155±16 μM. 6. Freshly cut human liver slices metabolized ZAL to a number of products including M1, M2 and DZAL. 7. Cimetidine inhibited ZAL metabolism in liver slices to M1 and M2, but not to DZAL. Kinetic analysis revealed that cimetidine was a competitive inhibitor of M2 formation in liver slices with an average (n = 2 preparations) Ki of 506 μM. 8. The results demonstrate that cimetidine can inhibit both the CYP3A and aldehyde oxidase pathways of ZAL metabolism in the human liver. Cimetidine appears to be a more potent inhibitor of aldehyde oxidase than of CYP3A forms and hence in vivo is likely to have a more marked effect on ZAL metabolism to M2 than on DZAL formation. 9. The results also demonstrate that precision-cut liver slices may be a useful model system for in vitro drug-interaction studies. Chemicals/CAS: Acetamides; Cimetidine, 51481-61-9; Enzyme Inhibitors; Hypnotics and Sedatives; Pyrimidines; zaleplon, 151319-34-5
Subject
Nutrition
Aldehyde oxidase
Cimetidine
Cytochrome P450 3A
Reduced nicotinamide adenine dinucleotide phosphate
Zaleplon
Cell fractionation
Drug inhibition
Drug metabolism
Human
Human cell
Human tissue
In vitro study
Liver metabolism
Liver microsome
Liver slice
Acetamides
Cimetidine
Cytosol
Dose-Response Relationship, Drug
Drug Interactions
Enzyme Inhibitors
Humans
Hypnotics and Sedatives
Inhibitory Concentration 50
Kinetics
Liver
Models, Chemical
Pyrimidines
Subcellular Fractions
Staphylococcus phage 3A
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DOI
https://doi.org/10.1080/00498250210158221
TNO identifier
42186
Source
Xenobiotica, 32 (10), 849-862
Document type
article