COMPARISON OF PREDICTION METHODS FOR IN VIVO CLEARANCE OF (S,S)-3-[3-(METHYLSULFONYL)PHENYL]-1-PROPYLPIPERIDINE HYDROCHLORIDE, A DOPAMINE D2 RECEPTOR ANTAGONIST, IN HUMANS
| Autor: | Shinji Yamazaki, Lisa N. Toth, J. Neil Duncan, Meredith L. Black |
|---|---|
| Rok vydání: | 2004 |
| Předmět: |
Adult
Male Quinidine Spectrometry Mass Electrospray Ionization CYP2D6 Metabolic Clearance Rate Drug Evaluation Preclinical Pharmaceutical Science Pharmacology Cytochrome P-450 CYP2D6 Inhibitors Rats Sprague-Dawley Animal data Dogs Piperidines Species Specificity Pharmacokinetics In vivo medicine Animals Humans Drug Interactions Sulfones Volume of distribution Receptors Dopamine D2 Chemistry Antagonist Middle Aged Rats Dopamine D2 Receptor Antagonists Macaca fascicularis Ketoconazole Cytochrome P-450 CYP2D6 Injections Intravenous Hepatocytes Haloperidol Female Chromatography Liquid medicine.drug |
| Zdroj: | Drug Metabolism and Disposition. 32:398-404 |
| ISSN: | 1521-009X 0090-9556 |
| Popis: | The purpose of this study is to investigate reliable prediction methods for in vivo pharmacokinetics and the likelihood of drug interactions with several cytochrome P450 inhibitors in humans for (S,S)-3-[3-(methylsulfonyl)phenyl]-1-propylpiperidine (PNU-96391). By allometric scaling of in vivo animal data, clearance of PNU-96391 in humans was over-predicted by 4-fold, half-life was under-predicted by 3-fold, and volume of distribution was accurately predicted. High correlation coefficients (>0.99) were observed for these parameters. Neither the in vitro-in vivo correlation approach nor the modified allometric scaling with maximum life span potential or brain weight accurately provided the predicted clearance value. Using an alternative method, based on normalization of in vitro human data with the ratio of in vivo to in vitro animal data, the in vivo clearance in humans was predicted to be 0.39 l/h/kg. This value correlated well with the in vivo value (0.43 l/h/kg). Regarding the interactions of PNU-96391 with cytochrome P450 inhibitors, only quinidine, haloperidol, and ketoconazole showed significant inhibition on the metabolic clearance of PNU-96391 in human hepatocytes. By comparing in vitro K(i) values with in vivo maximum unbound concentrations of the inhibitor, the increases in systemic exposure of PNU-96391 by coadministration of the inhibitors were estimated to be less than 1.5-fold. A preliminary comparison of pharmacokinetics of PNU-96391 between CYP2D6 extensive and poor metabolizers in the clinical study showed only a slight increase in systemic exposure in poor metabolizers (approximately 1.4-fold as area under the concentration-time curve). Therefore, clinically significant drug-drug interactions of PNU-96391 would be unlikely to occur with coadministration of CYP2D6 inhibitors. |
| Databáze: | OpenAIRE |
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