COMPARISON OF PREDICTION METHODS FOR IN VIVO CLEARANCE OF (<i>S</i>,<i>S</i>)-3-[3-(METHYLSULFONYL)PHENYL]-1-PROPYLPIPERIDINE HYDROCHLORIDE, A DOPAMINE D2 RECEPTOR ANTAGONIST, IN HUMANS

Yamazaki, Shinji; Toth, Lisa N.; Black, Meredith L.; Duncan, J. Neil

doi:10.1124/dmd.32.4.398

Cited by 7 publications

(9 citation statements)

References 29 publications

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“…In addition, we used Sprague-Dawley rats implanted with both jugular and portal vein cannulas. The estimates of CL and V ss of PNU96391 in the jugular vein were 2.4 l/h/kg and 2.7 l/kg, respectively, in the present study, which were very consistent with the values reported previously (Shobe et al, 2000;Yamazaki et al, 2004). Thus, the effects of the cannula implantation into both jugular and portal veins on the pharmacokinetics of PNU96391 seem to be negligible.…”

Section: Discussionsupporting

confidence: 82%

“…The hepatic availability (F h ) was estimated to be 43%, which was consistent with the oral bioavailability in jugular vein (F oral ϭ 40%) because the bioavailability in the portal vein (F a ⅐ F g ) was near complete (Ͼ90%). The blood/plasma concentration ratio of PNU96391 has been reported to be approximately unity (Yamazaki et al, 2004). Accordingly, the blood clearance of PNU96391 was calculated to be 2.4 l/h/kg, which accounted for approximately 60% of hepatic blood flow in rats (4.2 l/h/kg) (Lin et al, 1982).…”

Section: Discussionmentioning

confidence: 99%

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

Yamazaki

Toth²,

Kimoto³

et al. 2009

Drug Metab Dispos

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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...

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

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

Yamazaki

Toth²,

Kimoto³

et al. 2009

Drug Metab Dispos

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“…Zuegge et al (2001) used allometric scaling with correction for in-vitro hepatocyte CL int to predict the CL H for 22 compounds, and found 68% of predictions within 2-fold error and a maximum error of 10-fold. Yamasaki et al (2004) demonstrated that in-vitro hepatocyte CL int -corrected allometric scaling, but not allometric scaling (with and without brain weight and MLP correction), predicted the human invivo CL of a low CL compound well. Terelius et al (2001) used allometry for both observed and scaled (from hepatocyte data) in-vivo data, and concluded that pooling of data from different sources (in-vivo and in-vivo) was required to accurately assess the uncertainty in the predictions.…”

Section: Allometric Scaling With Correction For Interspecies CL Int Amentioning

confidence: 95%

“…To improve the predictability of the allometric scaling principle, corrections for species differences in in-vitro CL int and/ or plasma f u have been included (Boxenbaum 1980;Bonati et al 1984;Sawada et al 1985;Chiou & Hsu 1988;Paxton et al 1990;Chiou & Choi 1995;Lavé et al 1995bLavé et al ,1996aLavé et al , b, 1997aLavé et al , 1999aObach et al 1997;Sanwald-Ducray & Dow 1997;van Hoogdalem et al 1997;Mahmood 1998;Richter et al 1998;Ward et al 1999;Feng et al 2000;Terelius et al 2001;Zuegge et al 2001;Luttringer et al 2003;Yamasaki et al 2004;Tang & Mayersohn 2005). Chiou & Hsu (1988) found good predictability of CL u (from rat to man) and poor predictability of CL for 15 extensively metabolized compounds.…”

Section: Allometric Scaling With Correction For Interspecies CL Int Amentioning

confidence: 99%

Prediction of human pharmacokinetics—evaluation of methods for prediction of hepatic metabolic clearance

Fagerholm

2007

Journal of Pharmacy and Pharmacology

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Methods for prediction of hepatic clearance (CL(H)) in man have been evaluated. A physiologically-based in-vitro to in-vivo (PB-IVIV) method with human unbound fraction in blood (f(u, bl)) and hepatocyte intrinsic clearance (CL(int))-data has a good rationale and appears to give the best predictions (maximum approximately 2-fold errors; < 25% errors for half of CL-predictions; appropriate ranking). Inclusion of an empirical scaling factor is, however, needed, and reasons include the use of cryo-preserved hepatocytes with low activity, and inappropriate CL(int)- and f(u, bl)-estimation methods. Thus, an improvement of this methodology is possible and required. Neglect of f(u, bl) or incorporation of incubation binding does not seem appropriate. When microsome CL(int)-data are used with this approach, the CL(H) is underpredicted by 5- to 9-fold on average, and a 106-fold underprediction (attrition potential) has been observed. The poor performance could probably be related to permeation, binding and low metabolic activity. Inclusion of scaling factors and neglect of f(u, bl) for basic and neutral compounds improve microsome predictions. The performance is, however, still not satisfactory. Allometry incorrectly assumes that the determinants for CL(H) relate to body weight and overpredicts human liver blood flow rate. Consequently, allometric methods have poor predictability. Simple allometry has an average overprediction potential, > 2-fold errors for approximately 1/3 of predictions, and 140-fold underprediction to 5800-fold overprediction (potential safety risk) range. In-silico methodologies are available, but these need further development. Acceptable prediction errors for compounds with low and high CL(H) should be approximately 50 and approximately 10%, respectively. In conclusion, it is recommended that PB-IVIV with human hepatocyte CL(int) and f(u, bl) is applied and improved, limits for acceptable errors are decreased, and that animal CL(H)-studies and allometry are avoided.

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“…Among these parameters, CL plays a central role because it relates to both the drug's half-life (t 1/2 ) and oral bioavailability (F oral ), whereas V ss and F abs are also required to fully characterize the dosing regimen such as dose size and frequency. Methods of predicting CL in humans include species scaling by allometry (Boxenbaum, 1984;Mordenti, 1986;Ings, 1990), in vitro-in vivo extrapolation (IVIVE) (Houston and Carlile, 1997;Obach et al, 1997;Rostami-Hodjegan and Tucker, 2007), and the combined use of in vivo animal and in vitro human data (Ubeaud et al, 1995;Lavé et al, 1999;Yamazaki et al, 2004). Allometric scaling is simply based on the similarity of anatomical, physiological, and biochemical variables across species including humans.…”

Section: Introductionmentioning

confidence: 99%

Prediction of Oral Pharmacokinetics of cMet Kinase Inhibitors in Humans: Physiologically Based Pharmacokinetic Model Versus Traditional One-Compartment Model

Yamazaki¹,

Skaptason²,

Romero³

et al. 2010

Drug Metab Dispos

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ABSTRACT:The objective of this study was to assess the physiologically based error) and PF04217903 (1.3-fold error) compared with the onecompartment PK model (1.8-and 1.9-fold errors, respectively). Of more importance, the simulated plasma concentration-time profiles of PF02341066 and PF04217903 by PBPK modeling seemed to be consistent with the observed profiles showing multiexponential declines, resulting in more accurate prediction of the apparent half-lives (t 1/2 ): the observed and predicted t 1/2 values were, respectively, 10 and 12 h for PF02341066 and 6.6 and 6.3 h for PF04217903. The predicted t 1/2 values by the one-compartment PK model were 17 h for PF02341066 and 1.9 h for PF04217903. Therefore, PBPK modeling has the potential to be more useful and reliable for the PK prediction of PF02341066 and PF04217903 in humans than the traditional one-compartment PK model. In summary, the present study has shown examples to indicate that the PBPK model can be used to predict PK profiles in humans.

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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

Abstract: This article is available online at http://dmd.aspetjournals.org ABSTRACT: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

Cited by 7 publications

References 29 publications

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

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

Prediction of human pharmacokinetics—evaluation of methods for prediction of hepatic metabolic clearance

Prediction of Oral Pharmacokinetics of cMet Kinase Inhibitors in Humans: Physiologically Based Pharmacokinetic Model Versus Traditional One-Compartment Model

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