Quantitative Prediction of in Vivo Drug Clearance and Drug Interactions From in Vitro Data on Metabolism, Together With Binding and Transport

K, Ito; Iwatsubo, Takafumi; Kanamitsu, Shin-ichi; Nakajima, Yukiko; Sugiyama, Yuichi

doi:10.1146/annurev.pharmtox.38.1.461

Cited by 259 publications

(181 citation statements)

References 73 publications

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“…For miconazole, the Ki values for CYP2C8 obtained in the present study (0.86 µM) was comparable to the reported IC50 value (0.33 µM), at a substrate concentration of nearly Km toward CYP2C19-mediated S-mephenytoin 4´-hydroxylation activity in HLM (32). When the substrate concentration is lower than the Km value, the ratio of intrinsic clearance (CLint) in the presence and absence of the inhibitor can be expressed by the following equation, independent of the inhibition type, except in the case of uncompetitive inhibition (33)(34)(35):…”

Section: Discussionsupporting

confidence: 81%

Substrate Specificity of Human Cytochrome P450 (CYP) 2C Subfamily and Effect of Azole Antifungal Agents on CYP2C8

Niwa¹,

Imagawa²

2016

J Pharm Pharm Sci

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-PURPOSE: The metabolic activities of aminopyrine N-demethylation and tolbutamide methylhydroxylation by the human hepatic cytochrome P450 (P450 or CYP) 2C subfamily were compared and the effects of azole antifungal agent on the drug-metabolizing activity of CYP2C8 were investigated. METHODS: Aminopyrine N-demethylation and tolbutamide methylhydroxylation by CYP2C8, CYP2C9, and CYP2C19 were determined by the previous reported methods. The effects of five azole antifungal agents, fluconazole, itraconazole, ketoconazole, miconazole, and voriconazole, on the aminopyrine N-demethylation activity by CYP2C8 were investigated. RESULTS: With regard to aminopyrine N-demethylation, CYP2C19 had the lowest Michaelis constant (Km) and CYP2C8 had the highest maximal velocity (Vmax) among the CYP2C subfamily members. The Vmax/Km values for CYP2C8 were the highest, followed by CYP2C19. For tolbutamide methylhydroxylation, the Km and Vmax for CYP2C19 were three and six times higher than the corresponding values for CYP2C9, and the Vmax/Km value for CYP2C19 was twice that for CYP2C9, whereas hydroxylated tolbutamide formed by CYP2C8 was not detected. Fluconazole, itraconazole, and voriconazole at a concentration of 2 or 10 µM neither inhibited nor stimulated CYP2C8-mediated aminopyrine Ndemethylation activity at substrate concentrations around the Km (5 mM). However, ketoconazole and miconazole noncompetitively inhibited CYP2C8-mediated aminopyrine N-demethylation with the inhibitory constant values of 1.98 and 0.86 µM, respectively. CONCLUSION: These results suggest that ketoconazole and miconazole might inhibit CYP2C8 clinically.

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Section: Discussionsupporting

confidence: 81%

Substrate Specificity of Human Cytochrome P450 (CYP) 2C Subfamily and Effect of Azole Antifungal Agents on CYP2C8

Niwa¹,

Imagawa²

2016

J Pharm Pharm Sci

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“…When the substrate concentration is much lower than the K m value, the degree of inhibition (R) can be expressed by the following equation, independent of the inhibition type, except in the case of uncompetitive inhibition, 23,24) Rϭ1/(1ϩI u /K i ) where I u is the unbound concentration of the inhibitor. Additionally, when the absorption rate is maximum, the maximum inflow concentration of the inhibitor into liver (I in,max ) can be expressed as,…”

Section: Resultsmentioning

confidence: 99%

Effect of Nilvadipine, a Dihydropyridine Calcium Antagonist, on Cytochrome P450 Activities in Human Hepatic Microsomes

Niwa

Shiraga

Hashimoto

et al. 2004

Biological & Pharmaceutical Bulletin

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“…After appropriate binding corrections, more potent hepatocyte inhibition (as evident by lower K i values) would suggest the involvement of hepatic transporters because a higher concentration of unbound drug available for enzyme inhibition can be achieved compared with a similar incubation concentration in microsomes (Ito et al, 1998). Alternatively, similar values would indicate that any hepatic accumulation results from intracellular binding or lysosomal trapping (Grime and Riley, 2006;Hallifax and Houston, 2007).…”

Section: Introductionmentioning

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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Quantitative Prediction of in Vivo Drug Clearance and Drug Interactions From in Vitro Data on Metabolism, Together With Binding and Transport

Cited by 259 publications

References 73 publications

Substrate Specificity of Human Cytochrome P450 (CYP) 2C Subfamily and Effect of Azole Antifungal Agents on CYP2C8

Substrate Specificity of Human Cytochrome P450 (CYP) 2C Subfamily and Effect of Azole Antifungal Agents on CYP2C8

Effect of Nilvadipine, a Dihydropyridine Calcium Antagonist, on Cytochrome P450 Activities in Human Hepatic Microsomes

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

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