Prediction of Human Clearance of Twenty-Nine Drugs from Hepatic Microsomal Intrinsic Clearance Data: An Examination of In Vitro Half-Life Approach and Nonspecific Binding to Microsomes
Abstract
Twenty-nine drugs of disparate structures and physicochemical properties were used in an examination of the capability of human liver microsomal lability data ("in vitro T(1/2)" approach) to be useful in the prediction of human clearance. Additionally, the potential importance of nonspecific binding to microsomes in the in vitro incubation milieu for the accurate prediction of human clearance was investigated. The compounds examined demonstrated a wide range of microsomal metabolic labilities with scaled intrinsic clearance values ranging from less than 0.5 ml/min/kg to 189 ml/min/kg. Microsomal binding was determined at microsomal protein concentrations used in the lability incubations. For the 29 compounds studied, unbound fractions in microsomes ranged from 0.11 to 1.0. Generally, basic compounds demonstrated the greatest extent of binding and neutral and acidic compounds the least extent of binding. In the projection of human clearance values, basic and neutral compounds were well predicted when all binding considerations (blood and microsome) were disregarded, however, including both binding considerations also yielded reasonable predictions. Including only blood binding yielded very poor projections of human clearance for these two types of compounds. However, for acidic compounds, disregarding all binding considerations yielded poor predictions of human clearance. It was generally most difficult to accurately predict clearance for this class of compounds; however the accuracy was best when all binding considerations were included. Overall, inclusion of both blood and microsome binding values gave the best agreement between in vivo clearance values and clearance values projected from in vitro intrinsic clearance data.
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Obach reported that human CL of neutral and basic compounds was adequately predicted with or without binding factors, but for acid compounds, excluding binding factors, human CL values were predicted with a high degree of error.
“Results showed that human CL of neutral and basic compounds was adequately predicted with or without binding factors. However, in case of acid compounds, excluding binding factors, human CL values were predicted with a high degree of error.”
From Interpretation of Non-Clinical Data for Prediction of Human Pharmacokinetic Parameters: In Vitro-In Vivo Extrapolation and Allometric Scaling (2019) · cites this paper as [62]
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- Authors
- Obach, R. S.
- Affiliations
- Pfizer (United States) (US)
- Corresponding author
- Obach, R. Scott
- ORCID
- Obach, R. Scott
- Venue
- Drug Metabolism and Disposition
- Publisher
- Elsevier BV
- Published
- 1999-11
- Volume
- 27
- Issue
- 11
- Pages
- 1350-1359
- ISSN
- 0090-9556 (ISSN-L)
- OpenAlex
- W2144465276
- Cited by
- 1,232
- References
- 1
- Citations by year
- 2026: 38 · 2025: 29 · 2024: 32 · 2023: 31 · 2022: 43 · 2021: 66 · 2020: 63 · 2019: 70 · 2018: 59 · 2017: 54 · 2016: 67 · 2015: 64 · 2014: 56 · 2013: 48 · 2012: 76
- FWCI
- 18.77
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Drug Metabolism and Disposition (publishedVersion)
- PubMed (publishedVersion)
- PubMed
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Keywords
- microsomal binding, unbound fraction, drug metabolism, acidic drugs, basic drugs, physicochemical properties
- MeSH terms
- Atmospheric Pressure, Chromatography, High Pressure Liquid, Cytochrome P-450 Enzyme System, Half-Life, Humans, Microsomes, Liver, Pharmacokinetics, Mass Spectrometry
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