Abstract
The search for new drugs is an extremely time-consuming and costly endeavor. Much of the time and cost are expended on generating data that support the efficacy and safety profiles of the drug. Because of ethical constraints, relevant pharmacological and toxicological assessments must be made in laboratory animals and in in vitro systems before human testing can begin. In support of the efficacy and safety evaluation during drug development, two fundamental challenges facing industrial drug metabolism scientists are (1) how to “scale-up” the pharmacokinetic data from animals to humans and (2) how to extrapolate the in vitro data to the in vivo situation. This review examines the applications and limitations of interspecies scaling and in vitroextrapolation in pharmacokinetics.
Footnotes
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Send reprint requests to: Dr. Jiunn H. Lin, Drug Metabolism, Merck Research Laboratories, WP 42–2, West Point, PA 19486. e-mail: jiunn_lin{at}merck.com
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↵2 Lin JH, Chen I-W and deLuna FA, unpublished data, 1996.
- Abbreviations used are::
- ADME
- absorption, distribution, metabolism and excretion
- F
- bioavailability
- fabs
- the fraction of dose absorbed from the gastrointestinal lumen
- fg
- the fraction of drug metabolized by the gut wall
- fh
- the fraction of drug metabolized by the liver
- Vd
- volume of distribution of total (bound + unbound) drug
- Vf
- volume of distribution of unbound drug
- Vmax
- the maximum velocity of metabolite formation
- KM
- Michaelis constant
- Ki
- inhibitory constant
- AUC
- area under plasma concentration curve
- P450
- cytochrome P450
- UGT
- uridine diphosphate glycosyltransferase
- AZT
- zidovudine
- HIV
- human immunodeficiency virus
- GFR
- glomerular filtration rate
- CLint
- intrinsic clearance
- CLH
- hepatic clearance
- The American Society for Pharmacology and Experimental Therapeutics
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Applications and Limitations of Interspecies Scaling and In Vitro Extrapolation in Pharmacokinetics
