Interspecies scaling: is a priori knowledge of cytochrome p450 isozymes involved in drug metabolism helpful in prediction of clearance in humans from animal data?
The objective of this study was to evaluate whether a priori knowledge of cytochrome P450 isozymes involved in drug metabolism coupled with Mahmood' and Balian's 'rule of exponents' can be helpful for the prediction of clearance in humans using animal data. The clearance of 27 randomly selected drugs metabolized by different isozymes were scaled up from the animal data (at least three animal species) obtained from the literature. Three methods were utilized to generate allometric equations to scale up the clearance values: (i) clearance vs body weight (simple allometry); (ii) product of the clearance and maximum life-span potential (MLP) vs body weight; and (iii) the product of clearance and brain weight vs body weight. The choice of one of the methods was based on the 'rule of exponents' as described by Mahmood and Balian. The results of this study indicate that the knowledge of a particular isozyme does not provide a guide for the failure or success of allometry for the prediction of clearance. There is no trend which indicates that the chances of accurate prediction of clearance for a given drug are comparatively higher or lower when they are metabolized by a particular isozyme.
Mahmood
I
I
Division of Pharmaceutical Evaluation I, Office of Clinical Pharmacology and Biopharmaceutics, Food & Drug Administration, Rockville, MD 20852, USA. Mahmoodi@CDER.FDA.GOV
D000284:Administration, Oral; D000818:Animals; D001835:Body Weight; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology*; D004285:Dogs; D006168:Guinea Pigs; D000882:Haplorhini; D006801:Humans; D007275:Injections, Intravenous; D008017:Life Expectancy; D008657:Metabolic Clearance Rate; D051379:Mice; D008954:Models, Biological; D010599:Pharmacokinetics; D011817:Rabbits; D051381:Rats; D015203:Reproducibility of Results
D003577:Cytochrome P-450 Enzyme System