Application of Stable Isotope Methodology in the Evaluation of the Pharmacokinetics of (S,S)-3-[3-(Methylsulfonyl)phenyl]-1-propylpiperidine Hydrochloride in Rats
| Autor: | Judith Skaptason, Janice Bower, Emi Kimoto, Timothy G. Heath, David Romero, Lisa N. Toth, Shinji Yamazaki |
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| Rok vydání: | 2009 |
| Předmět: |
Male
Hydrochloride Metabolite Administration Oral Pharmaceutical Science Pharmacology Intestinal absorption Rats Sprague-Dawley chemistry.chemical_compound Piperidines Pharmacokinetics Biotransformation Tandem Mass Spectrometry Animals Distribution (pharmacology) Tissue Distribution Sulfones Chromatography High Pressure Liquid ADME Models Statistical Chromatography Rats Dopamine D2 Receptor Antagonists Intestinal Absorption chemistry Area Under Curve Injections Intravenous Quantitative analysis (chemistry) |
| Zdroj: | Drug Metabolism and Disposition. 37:937-945 |
| ISSN: | 1521-009X 0090-9556 |
| DOI: | 10.1124/dmd.108.025478 |
| Popis: | The primary objective of this study was to demonstrate the use of stable isotope (SI)-labeled compound as an approach for pharmacokinetic analysis such as fraction absorbed, hepatic extraction ratio, and fraction metabolized from the parent drug to a metabolite. (S,S)-3-[3-(Methylsulfonyl)phenyl]-1-propylpiperidine hydrochloride (PNU96391) was selected as the model compound because of its simple biotransformation pathway, i.e., the predominant metabolic pathway to the N-despropyl metabolite (M1), which makes it a suitable candidate. The second objective was to fully characterize the pharmacokinetics of PNU96391 in rats using the SI coadministration approach with quantitative analysis by liquid chromatography-tandem mass spectrometry. Overall the present study showed that 1) absorption of PNU96391 from the gastrointestinal tract was near complete (>90% of the dose), 2) PNU96391 was predominantly metabolized to M1 (approximately 70% of the dose), and 3) M1 was exclusively eliminated into urine with negligible biotransformation (ratio of renal clearance to plasma clearance approximately 0.9). Therefore, the present study demonstrated the utility of the SI methodology for characterizing the pharmacokinetics of a compound within the drug discovery and development process. Furthermore, the compartmental pharmacokinetic modeling provided insights into the disposition and biotransformation rates of PNU96391 and M1, suggesting that the modeling could add further advantages to the SI coadministration approach. Despite the greater availability of SI-labeled compounds, absorption, distribution, metabolism, and excretion (ADME) scientists have yet to take full advantage of the potential use of these analogs for mechanistic ADME studies. These SI-labeled compounds can be used more widely to gain a better understanding of ADME properties in drug discovery and development. |
| Databáze: | OpenAIRE |
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