Prediction of in vivo drug metabolism in the human liver from in vitro metabolism data

Iwatsubo, Takafumi; Hirota, Noriko; Ooie, Tsuyoshi; Suzuki, Hiroshi; Shimada, Noriaki; Chiba, Kazuhiro; Ishizaki, Takashi; Green, Carol E.; Tyson, Charles A.; Sugiyama, Yuichi

doi:10.1016/s0163-7258(96)00184-2

Cited by 409 publications

(302 citation statements)

References 60 publications

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“…In vitro drug metabolism kinetic parameters can provide an estimate of in vivo CL int via "scaling" with established biological scaling factors (SFs) e.g., hepatocellularity for isolated hepatocytes, or a SF for microsomes based on incomplete microsomal recovery from human liver tissue using the cytochrome P450 (P450) content in homogenate and microsomes (Houston, 1984). CL int may subsequently be used to provide an estimate of hepatic clearance (CL h ) using several liver models (Houston, 1984;Ito and Houston, 2004).To date, the more extensive analyses of human clearance predictions have concentrated on P450 substrates, and data have therefore been generated in human liver microsomes (Iwatsubo et al, 1997;Obach, 1999;Naritomi et al, 2001). In general, these studies have been less comprehensive in the range of approaches investigated, with only occasional attention given to chemical class (Obach et al, 1997).…”

mentioning

confidence: 99%

“…Existing methods for the prediction of drug clearance in humans involve the use of in vitro human metabolic stability (intrinsic clearance, CL int ) data (Iwatsubo et al, 1997), consideration of preclinical animal data (Boxenbaum, 1982), or a combination of these approaches (Lave et al, 1997a;Naritomi et al, 2001). In vitro drug metabolism kinetic parameters can provide an estimate of in vivo CL int via "scaling" with established biological scaling factors (SFs) e.g., hepatocellularity for isolated hepatocytes, or a SF for microsomes based on incomplete microsomal recovery from human liver tissue using the cytochrome P450 (P450) content in homogenate and microsomes (Houston, 1984).…”

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confidence: 99%

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A Unified Model for Predicting Human Hepatic, Metabolic Clearance From in Vitro Intrinsic Clearance Data in Hepatocytes and Microsomes

Riley

McGinnity²,

Austin³

2005

Drug Metab Dispos

337

289

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ABSTRACT:The aim of this study was to evaluate a unified method for predicting human in vivo intrinsic clearance (CL int, in vivo ) and hepatic clearance (CL h ) from in vitro data in hepatocytes and microsomes by applying the unbound fraction in blood (fu b ) and in vitro incubations (fu inc ). Human CL int, in vivo was projected using in vitro data together with biological scaling factors and compared with the unbound intrinsic clearance (CL int, ub, in vivo ) estimated from clinical data using liver models with and without the various fu terms. For incubations conducted with fetal calf serum (n ‫؍‬ 14), the observed CL int, in vivo was modeled well assuming fu inc and fu b were equivalent. CL int, ub, in vivo was predicted best using both fu b Existing methods for the prediction of drug clearance in humans involve the use of in vitro human metabolic stability (intrinsic clearance, CL int ) data (Iwatsubo et al., 1997), consideration of preclinical animal data (Boxenbaum, 1982), or a combination of these approaches (Lave et al., 1997a;Naritomi et al., 2001). In vitro drug metabolism kinetic parameters can provide an estimate of in vivo CL int via "scaling" with established biological scaling factors (SFs) e.g., hepatocellularity for isolated hepatocytes, or a SF for microsomes based on incomplete microsomal recovery from human liver tissue using the cytochrome P450 (P450) content in homogenate and microsomes (Houston, 1984). CL int may subsequently be used to provide an estimate of hepatic clearance (CL h ) using several liver models (Houston, 1984;Ito and Houston, 2004).To date, the more extensive analyses of human clearance predictions have concentrated on P450 substrates, and data have therefore been generated in human liver microsomes (Iwatsubo et al., 1997;Obach, 1999;Naritomi et al., 2001). In general, these studies have been less comprehensive in the range of approaches investigated, with only occasional attention given to chemical class (Obach et al., 1997). Interestingly, these reports have also assessed the ability to predict human CL h rather than the more fundamental parameter, CL int , as advocated initially (Houston, 1984;Ito and Houston, 2004). Some controversy also still exists over use of fu inc , with some laboratories having suggested that fu inc and fu b may cancel, negating their inclusion in liver models (Obach et al., 1997). Recent reports have challenged this assumption (Obach, 1999;Austin et al., 2002) and perhaps suggest that consideration of CL h rather than CL int, in vivo may desensitize such analyses, particularly to errors associated with higher enzyme activities (Ito and Houston, 2004).The aim of this study was to investigate direct in vitro-in vivo scaling of human in vitro data generated in hepatocytes and microsomes for predicting human clearance in vivo by applying recently described models for estimating fu inc (Austin et al., 2002(Austin et al., , 2005. To provide a more mechanistic insight, in vitro human CL int data were compiled from recent in-house and published stud...

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confidence: 99%

mentioning

confidence: 99%

A Unified Model for Predicting Human Hepatic, Metabolic Clearance From in Vitro Intrinsic Clearance Data in Hepatocytes and Microsomes

Riley

McGinnity²,

Austin³

2005

Drug Metab Dispos

337

289

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“…Many studies have shown how in vivo CL in the rat or dog can be predicted successfully from the in vitro data for the same species [34]. A similar approach can be undertaken for human CL predictions, although for certain classes of compound there is a lack of correlation between the CLi value derived in vitro using human microsomes or hepatocytes and that Human microdose study of GSK269984A calculated in vivo [43]. Ostensibly, the present data would lend support to other studies that have shown how the prediction of human CL in vivo can be improved by the appropriate incorporation of in vitro data.For example, predictions of human CL based on allometric scaling from pre-clinical in vivo data can be improved by first normalizing in vivo CL values using the respective in vitro CLi values [44], while other investigators have proposed the initial correction of in vitro human CLi using a scaling factor derived from animal studies [45,46].…”

Section: Figurementioning

confidence: 99%

Human microdose evaluation of the novel EP1 receptor antagonist GSK269984A

Ostenfeld

Beaumont

Bullman

et al. 2012

Brit J Clinical Pharma

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• The microdose administration of novel drug candidates to humans in early development is currently undergoing evaluation as a cost‐efficient approach to the early assessment of pharmacokinetics (PK) before the commitment of resources required to support formal phase 1 studies.• The microdose approach assumes that PK can be extrapolated linearly over the full range of exposures achieved with sub‐pharmacological doses up to the therapeutic dose range.• Few microdose studies have been undertaken in the context of pharmaceutical drug development and their precise role in the selection of candidates for further clinical evaluation at therapeutic doses has yet to be fully substantiated.WHAT THIS STUDY ADDS• The present study describes the elective application of a human microdose study with a novel EP1 receptor antagonist, GSK269984A, to address a critical development liability posed by uncertainty with respect to the predicted human PK profile.• Microdose data revealed a favourable PK profile, consistent with a clinically acceptable dosing regimen. These data support the value of undertaking a microdose study early in the drug discovery process to facilitate risk evaluation and to enable decision‐making.AIM The primary objective was to evaluate the pharmacokinetics (PK) of the novel EP1 antagonist GSK269984A in human volunteers after a single oral and intravenous (i.v.) microdose (100 µg).METHOD GSK269984A was administered to two groups of healthy human volunteers as a single oral (n= 5) or i.v. (n= 5) microdose (100 µg). Blood samples were collected for up to 24 h and the parent drug concentrations were measured in separated plasma using a validated high pressure liquid chromatography‐tandem mass spectrometry method following solid phase extraction.RESULTS Following the i.v. microdose, the geometric mean values for clearance (CL), steady‐state volume of distribution (Vss) and terminal elimination half‐life (t1/2) of GSK269984A were 9.8 l h−1, 62.8 l and 8.2 h. Cmax and AUC(0,∞) were 3.2 ng ml−1 and 10.2 ng ml−1 h, respectively; the corresponding oral parameters were 1.8 ng ml−1 and 9.8 ng ml−1 h, respectively. Absolute oral bioavailability was estimated to be 95%. These data were inconsistent with predictions of human PK based on allometric scaling of in vivo PK data from three pre‐clinical species (rat, dog and monkey).CONCLUSION For drug development programmes characterized by inconsistencies between pre‐clinical in vitro metabolic and in vivo PK data, and where uncertainty exists with respect to allometric predictions of the human PK profile, these data support the early application of a human microdose study to facilitate the selection of compounds for further clinical development.

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“…2. (2) Where V max,vitro is the in vitro maximal rate of metabolism and K m,vitro is the in vitro Michaelis constant for the drug-enzyme interaction. A-CYP vivo is the in vivo amount of CYP and C E is the drug concentration at the enzyme site.…”

Section: Quantitation Of Cyp1a2 In Hepatic Microsomesmentioning

confidence: 99%

“…1) It has been suggested that the in vivo intrinsic clearance by hepatic metabolism can be predicted from in vitro metabolism data by the use of either liver microsomes or a recombinant system of human CYP isozymes. 2,3) Previously, we developed a novel method for determining drug metabolism capacity based on a pharmacokinetic estimation of the quantity of CYP in vivo (PKCYP-test). By using a specific probe, the drug metabolism capacity of each CYP isozyme can be estimated from the PKCYP-test incorporating the apparent liver-to-blood free concentration gradient in vivo (qg).…”

mentioning

confidence: 99%

Application of the PKCYP-test in Cases of Altered CYP1A2 for Multiple CYP Systems in Rat Models of Disease.

Matsunaga¹,

Hattori²,

Iizasa³

et al. 2001

Biological & Pharmaceutical Bulletin

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In order to evaluate the drug metabolism capacity of individual patients, selective substrate probes have been used in vivo to identify the cytochrome P450 (CYP) isozymes involved in a variety of drug metabolism processes. 1) It has been suggested that the in vivo intrinsic clearance by hepatic metabolism can be predicted from in vitro metabolism data by the use of either liver microsomes or a recombinant system of human CYP isozymes. 2,3) Previously, we developed a novel method for determining drug metabolism capacity based on a pharmacokinetic estimation of the quantity of CYP in vivo (PKCYP-test). By using a specific probe, the drug metabolism capacity of each CYP isozyme can be estimated from the PKCYP-test incorporating the apparent liver-to-blood free concentration gradient in vivo (qg). 4) In rats whose CYP1A2 level has been induced by the administration of 3-methylcholanthrene (MCtreated rats), the amount of CYP1A2 could be predicted by the PKCYP-test using acetanilide as the probe. Furthermore, caffeine clearance could also be predicted by using the predicted amount of CYP1A2. However, there were some differences between observed and predicted values as far as the amount of CYP1A2 and caffeine clearance were concerned.Both acetanilide and caffeine have been reported to be metabolized mainly by CYP1A2 in rats. 5,6) However, there is a contradictory report that another CYP isozyme is also involved in the metabolism of caffeine. 7) Since CYP1A2 participates mainly in the metabolism of both acetanilide and caffeine in MC-treated rats, the error in predicting the amount of CYP1A2 and caffeine clearance may be negligible. It is anticipated that the role of other CYP isozymes in their metabolism might have little effect on the prediction of the amount of CYP1A2 and caffeine clearance in other models in which the CYP1A2 enzyme level is reduced. Since there are many patients with reduced CYP levels, there is a need to investigate the application of the PKCYP-test to the reduced CYP model. Moreover, it is still unclear if the PKCYP-test can be applied to drugs that are metabolized by multiple CYP isozymes.It has been reported that the amount of CYP is reduced both in rats fed a choline-deficient diet and in aged rats, and the amount of CYP in these rat models is regulated differently by each CYP isozyme. [8][9][10][11] In order to examine the application of the PKCYP-test to drugs that are metabolized by multiple CYP isozymes and/or in models with reduced CYP levels, we examined the application of the PKCYP-test to the clearance of acetanilide and caffeine mediated by CYP1A2 using rats fed a choline-deficient diet and aged rats. MATERIALS AND METHODSMaterials Chemicals were obtained from the following sources: acetanilide, p-hydroxyacetanilide, caffeine, theobromine, and theophylline were from Wako Pure Chemicals (Osaka, Japan); 3-methylcholanthrene (MC), 1,7-dimethylxanthine and 1,3,7-trimethyluric acid were from Sigma Chemical Co. (St. Louis, MO, U.S.A.); [8-14 C] caffeine was from American Radiolabeled Chemica...

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Prediction of in vivo drug metabolism in the human liver from in vitro metabolism data

Cited by 409 publications

References 60 publications

A Unified Model for Predicting Human Hepatic, Metabolic Clearance From in Vitro Intrinsic Clearance Data in Hepatocytes and Microsomes

A Unified Model for Predicting Human Hepatic, Metabolic Clearance From in Vitro Intrinsic Clearance Data in Hepatocytes and Microsomes

Human microdose evaluation of the novel EP1 receptor antagonist GSK269984A

Application of the PKCYP-test in Cases of Altered CYP1A2 for Multiple CYP Systems in Rat Models of Disease.

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