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In vitro characterization of sarizotan metabolism: hepatic clearance, identification and characterization of metabolites, drug-metabolizing enzyme identification, and evaluation of cytochrome p450 inhibition.
- Source :
-
Drug metabolism and disposition: the biological fate of chemicals [Drug Metab Dispos] 2010 Jun; Vol. 38 (6), pp. 905-16. Date of Electronic Publication: 2010 Mar 10. - Publication Year :
- 2010
-
Abstract
- In vitro biotransformation studies of sarizotan using human liver microsomes (HLM) showed aromatic and aliphatic monohydroxylation and dealkylation. Recombinant cytochromes P450 (P450) together with P450-selective inhibitors in HLM/hepatocyte cultures were used to evaluate the relative contribution of different P450s and revealed major involvement of CYP3A4, CYP2C9, CYP2C8, and CYP1A2 in sarizotan metabolism. The apparent K(m, u) and V(max) of sarizotan clearance, as investigated in HLM, were 9 microM and 3280 pmol/mg/min, predicting in vivo hepatic clearance of 0.94 l/h, which indicates that sarizotan is a low-clearance compound in humans and suggests nonsaturable metabolism at the targeted plasma concentration (< or =1 microM). This finding is confirmed by the reported human clearance (CL/F of 3.6-4.4 l/h) and by the dose-linear area under the curve increase observed with doses up to 25 mg. The inhibitory effect of sarizotan toward six major P450s was evaluated using P450-specific marker reactions in pooled HLM. K(i, u) values of sarizotan against CYP2C8, CYP2C19, and CYP3A4 were >10 microM, whereas those against CYP2D6 and CYP1A2 were 0.43 and 8.7 microM, respectively. Based on the estimates of sarizotan concentrations at the enzyme active sites, no clinically significant drug-drug interactions (DDIs) due to P450 inhibition are expected. This result has been confirmed in human DDI studies in which no inhibition of five major P450s was observed in terms of marker metabolite formation.
- Subjects :
- Aryl Hydrocarbon Hydroxylases isolation & purification
Biotransformation
Cytochrome P-450 CYP2B6
Cytochrome P-450 CYP2C19
Cytochrome P-450 CYP2C9
Cytochrome P-450 CYP2D6 metabolism
Cytochrome P-450 CYP3A metabolism
Cytochrome P-450 Enzyme Inhibitors
Humans
Liver enzymology
Metabolic Clearance Rate
Microsomes, Liver enzymology
Organic Chemicals metabolism
Organic Chemicals pharmacology
Oxidoreductases, N-Demethylating metabolism
Aryl Hydrocarbon Hydroxylases metabolism
Cytochrome P-450 Enzyme System isolation & purification
Hypoglycemic Agents pharmacology
Prodrugs metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1521-009X
- Volume :
- 38
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Drug metabolism and disposition: the biological fate of chemicals
- Publication Type :
- Academic Journal
- Accession number :
- 20219851
- Full Text :
- https://doi.org/10.1124/dmd.109.029835