Abstract
Identifying any extrahepatic excretion phenomenon in preclinical species is crucial for an accurate prediction of the pharmacokinetics in man. This understanding is particularly key for drugs with a small volume of distribution, because they require an especially low total clearance to be suitable for a once-a-day dosing regimen in man. In this study, three animal scaling techniques were applied for the prediction of the human renal clearance of 36 diverse drugs that show active secretion or net reabsorption: 1) direct correlations between renal clearance in man and each of the two main preclinical species (rat and dog); 2) simple allometry; and 3) Mahmood's renal clearance scaling method. The results show clearly that the predictions to man for the methods are improved significantly when corrections are made for species differences in plasma protein binding. Overall, the most accurate predictions were obtained by using a direct correlation with the dog renal clearance after correcting for differences in plasma protein binding and kidney blood flow (r2 = 0.84), where predictions, on average, were within 2-fold of the observed renal clearance values in human.
Footnotes
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.110.037267.
↵ The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.
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ABBREVIATIONS:
- GFR
- glomerular filtration rate
- CLr
- renal clearance
- FCIM
- free fraction corrected intercept method
- fu
- unbound plasma fraction
- KBF
- kidney blood flow
- PPB
- plasma protein binding
- rmse
- root mean square error
- afe
- average fold error
- OAT
- organic anion transporter
- oatp1
- organic anion-transporting polypeptide 1.
- Received November 16, 2010.
- Accepted February 28, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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