Prediction of Hepatic Clearance from Microsomes, Hepatocytes, and Liver Slices

Houston, J. Brian; Carlile, David

doi:10.3109/03602539709002237

Cited by 272 publications

(203 citation statements)

References 15 publications

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“…of the parameters. Theophylline metabolic parameters from microsomal and hepatocyte incubations were scaled and are expressed as "per gram of liver" using the scaling factors 60 mg of protein/g of liver and 109 ϫ 10 6 cells/g of liver (Houston and Carlile, 1997).…”

Section: Methodsmentioning

confidence: 99%

Comparative Use of Isolated Hepatocytes and Hepatic Microsomes for Cytochrome P450 Inhibition Studies: Transporter-Enzyme Interplay

Brown¹,

Wilby²,

Alder³

et al. 2010

Drug Metab Dispos

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ABSTRACT:Accurate assignment of the concentration of victim drug/inhibitor available at the enzyme active site, both in vivo and within an in vitro incubation, is an essential requirement in rationalizing and predicting drug-drug interactions. Inhibitor accumulation within the liver, whether as a result of active transport processes or intracellular binding, may best be accounted for using hepatocytes rather than hepatic microsomes to estimate in vitro inhibitory potency. The aims of this study were to compare K i values determined in rat liver microsomes and freshly isolated rat hepatocytes of four cytochrome P450 (P450) inhibitors (clarithromycin, enoxacin, nelfinavir, and saquinavir) with known hepatic transporter involvement and a range of uptake (cell/medium concentration ratios 20-3000) and clearance (10-1200 l/min/10 6 cells) properties.Inhibition studies were performed using two well established P450 probe substrates (theophylline and midazolam). Comparison of unbound K i values showed marked differences between the two in vitro systems for inhibition of metabolism. In two cases (clarithromycin and enoxacin, both low-clearance drugs), inhibitory potency in hepatocytes markedly exceeded that in microsomes (10-to 20-fold), and this result was consistent with their high cell/medium concentration ratios. For nelfinavir and saquinavir (high-clearance, extensively metabolized drugs), the opposite trend was seen in the K i values: despite very high cell/medium concentration ratios, stronger inhibition was evident within microsomal preparations. Hence, the consequences of hepatic accumulation resulting from uptake transporters vary according to the clearance of the inhibitor. This study demonstrates that transporter-enzyme interplay can result in differences in inhibitory potency between microsomes and hepatocytes and hence drug-drug interaction predictions that are not always intuitive.

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Section: Methodsmentioning

confidence: 99%

Comparative Use of Isolated Hepatocytes and Hepatic Microsomes for Cytochrome P450 Inhibition Studies: Transporter-Enzyme Interplay

Brown¹,

Wilby²,

Alder³

et al. 2010

Drug Metab Dispos

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show abstract

“…Alternative liver models such as the parallel tube model are also available, selection of which might be determined by the hepatic extraction ratio; however, in our experience alternative models offer limited improvement over the well-stirred model [24,25]. In our approach, clearance for compounds that are believed to be primarily eliminated through hepatic pathways (based on human in vitro and preclinical PK data) is predicted using IVIVE.…”

Section: Prediction Of Clearancementioning

confidence: 99%

Application of IVIVE and PBPK modeling in prospective prediction of clinical pharmacokinetics: strategy and approach during the drug discovery phase with four case studies

Chen¹,

Jin²,

Mukadam³

et al. 2012

Biopharm & Drug Disp

102

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Prospective simulations of human pharmacokinetic (PK) parameters and plasma concentration-time curves using in vitro in vivo extrapolation (IVIVE) and physiologically based pharmacokinetic (PBPK) models are becoming a vital part of the drug discovery and development process. This paper presents a strategy to deliver prospective simulations in support of clinical candidate nomination. A three stage approach of input parameter evaluation, model selection and multiple scenario simulation is utilized to predict the key components influencing human PK; absorption, distribution and clearance. The Simcyp W simulator is used to illustrate the approach and four compounds are presented as case studies. In general, the prospective predictions captured the observed clinical data well. Predicted C max was within 2-fold of observed data for all compounds and AUC was within 2-fold for all compounds following a single dose and three out of four compounds following multiple doses. Similarly, t max was within 2-fold of observed data for all compounds. However, C last was less accurately captured with two of the four compounds predicting C last within 2-fold of observed data following a single dose. The trend in results was towards overestimation of AUC and C last , this was particularly apparent for compound 2 for which clearance was likely underestimated via IVIVE. The prospective approach to simulating human PK using IVIVE and PBPK modeling outlined here attempts to utilize all available in silico, in vitro and in vivo preclinical data in order to determine the most appropriate assumptions to use in prospective predictions of absorption, distribution and clearance to aid clinical candidate nomination.

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“…However, it is often difficult to choose the best IVIVE method based on animal data. A number of investigators have reported hepatocytes to be a superior system for CL prediction, with microsomes also providing reasonable data (Houston and Carlile, 1997;Obach, 1999;Naritomi et al, 2003). Both microsomes and hepatocytes were used in the present study to investigate the IVIVE approach as oxidative biotransformation was considered to be the major clearance pathway because 1) PF02341066 and PF04217903 were mainly metabolized to oxidative metabolites across species with little qualitative species differences in metabolite profiles (in house data) and 2) the contributions of urinary and biliary excretions of PF02341066 (Ͻ1 and 15% of the dose as parent drug, respectively) and PF04217903 (Ͻ1 and 5% of the dose, respectively) to systemic clearance were minimal in preclinical species.…”

Section: Discussionmentioning

confidence: 99%

“…Although allometric scaling is an empirical approach, it has been widely used and provided reliable predictions for a number of highly metabolized and renally excreted drugs (Boxenbaum, 1984;Mordenti, 1986;Mahmood and Balian, 1996). Over the last two decades, the methods for extrapolating in vivo CL from in vitro data (i.e., IVIVE) have been applied extensively with the increased availability of human liver samples (e.g., microsomes, hepatocytes, liver slices, and others) and have demonstrated prediction accuracy for metabolic CL of low to high hepatic extraction compounds (Houston and Carlile, 1997;Obach et al, 1997;Obach, 1999;Riley et al, 2005;Shiran et al, 2006). In recent years, there has been growing interest in the physiologically based pharmacokinetic (PBPK) model, which provides the disposition profiles in various species to be predicted from physicobiochemical properties of compounds with the species-specific physiological parameters (Jones et al, 2006;De Buck et al, 2007;Lavé et al, 2007;Nestorov, 2007).…”

Section: Introductionmentioning

confidence: 99%

“…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%

See 1 more Smart Citation

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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Prediction of Hepatic Clearance from Microsomes, Hepatocytes, and Liver Slices

Cited by 272 publications

References 15 publications

Comparative Use of Isolated Hepatocytes and Hepatic Microsomes for Cytochrome P450 Inhibition Studies: Transporter-Enzyme Interplay

Comparative Use of Isolated Hepatocytes and Hepatic Microsomes for Cytochrome P450 Inhibition Studies: Transporter-Enzyme Interplay

Application of IVIVE and PBPK modeling in prospective prediction of clinical pharmacokinetics: strategy and approach during the drug discovery phase with four case studies

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

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