Application of Stable Isotope Methodology in the Evaluation of the Pharmacokinetics of (S,S)-3-[3-(Methylsulfonyl)phenyl]-1-propylpiperidine Hydrochloride in Rats

Abstract

ABSTRACT: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 Ϸ0.9). 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.Therapeutic drugs are most often administered orally, and the majority of these are intended to act systemically. A number of important factors limit systemic availability of orally administered drugs; therefore, an early estimation of oral bioavailability of new chemical entities is often desired to provide guidance to the iterative chemistry effort. Furthermore, because oral bioavailability is primarily limited by either high first-pass hepatic extraction or low delivery to the portal circulation (because of low solubility, poor absorption, and/or intestinal extraction), it is often of interest to determine the relative importance of these two factors (Kwan, 1997). The contribution of each factor is assessed indirectly by comparing exposure levels obtained by administration through different routes (Gibaldi et al., 1971;Rowland, 1972) and/or from different blood sampling sites (Ward, et al., 2001;Murakami et al., 2003). Such information is essential as a guide to chemical modifications aimed to optimize the oral bioavailability. Furthermore, pharmacokinetic evaluations of metabolites are often important in drug discovery and development, particularly when drug e...

Physiological Modeling to Understand the Impact of Enzymes and Transporters on Drug and Metabolite Data and Bioavailability Estimates

“…One method is to compare the drug exposure (AUC) following the dosing into the intestine lumen (po), the superior mesenteric artery, portal vein, and peripheral vein (iv) (39). Alternately, blood samples may be taken from the peripheral vein, artery and portal vein following iv and po dosing to construct the various AUCs in the estimation of F abs , F I , and F H (40). With the use of isotopically labeled drug, one is also able to administer the drug labeled with the stable isotope via one route and the unlabeled drug via another route simultaneously to yield the AUCs of labeled and unlabeled drug from the same subject so as to minimize the interindividual and intraindividual variation (40).…”

The Dopamine Stabilizer (−)-OSU6162 Occupies a Subpopulation of Striatal Dopamine D2/D3 Receptors: An [11C]Raclopride PET Study in Healthy Human Subjects

“…After 5 min of ultracentrifugation (20 000 g), the supernatant was transferred to a 2.0-ml amber screw cap vial with a 200-ml insert. Plasma concentrations of ( À )-OSU6162 were quantitatively determined by LC-MS/MS using an optimized stable isotope dilution method (Yamazaki et al, 2009). The injection volume was 2 ml, and [ 2 H 7 ]( À )-OSU6162 (Syntagon, Södertälje, Sweden) was used as an internal standard.…”