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 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.
Footnotes
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.109.029835.
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The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.
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ABBREVIATIONS:
- SZ
- sarizotan
- AUC
- area under the curve
- Cmax
- maximum plasma concentration
- tmax
- time of maximum plasma concentration
- NCE
- new chemical entity
- P450
- cytochrome P450
- DDI
- drug-drug interaction
- PK
- pharmacokinetic(s)
- HLM
- human liver microsome(s)
- ABT
- aminobenzotriazole
- EMD 148107
- (−)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-6-hydroxychromane, dihydrochloride
- EMD 329989
- 2R,4R/S)-2-({[5-(4-fluorophenyl)-pyridine-3-ylmethyl]-amino}-methyl)-chromane-4-ol
- EMD 50929
- 3-(4-fluorophenyl)-pyridine-5-carbonic acid
- LC
- liquid chromatography
- MS/MS
- tandem mass spectrometry
- HPLC
- high-pressure liquid chromatography
- RT
- retention time
- Ki, u
- inhibitory constant considering fu in microsomal incubations
- Km, u
- unbound Michaelis-Menten constant.
- Received August 21, 2009.
- Accepted March 10, 2010.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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