RT Journal Article
SR Electronic
T1 In Vitro Characterization of Sarizotan Metabolism: Hepatic Clearance, Identification and Characterization of Metabolites, Drug-Metabolizing Enzyme Identification, and Evaluation of Cytochrome P450 Inhibition
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 905
OP 916
DO 10.1124/dmd.109.029835
VO 38
IS 6
A1 Dieter Gallemann
A1 Elmar Wimmer
A1 Constance C. Höfer
A1 Achim Freisleben
A1 Markus Fluck
A1 Bernhard Ladstetter
A1 Hugues Dolgos
YR 2010
UL http://dmd.aspetjournals.org/content/38/6/905.abstract
AB 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 Km, u and Vmax of sarizotan clearance, as investigated in HLM, were 9 μM 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 (≤1 μM). 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. Ki, u values of sarizotan against CYP2C8, CYP2C19, and CYP3A4 were >10 μM, whereas those against CYP2D6 and CYP1A2 were 0.43 and 8.7 μM, 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. Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics