CORRELATION OF PLASMA-CLEARANCE OF 54 EXTENSIVELY METABOLIZED DRUGS BETWEEN HUMANS AND RATS - MEAN ALLOMETRIC COEFFICIENT OF 0.66

Purpose. To evaluate the distribution of allometric exponents for rela tionship of total plasma clearance of 54 extensively metabolized drugs , with wide-ranging linear clearance values, between humans and rats, to provide a rationale for the observed data, and to discuss potential significance of the findings. Methods. Human and rat plasma clearance values of 54 drugs with markedly different physicochemical properties were obtained from the literature. Standard allometric analysis was p erformed for each drug using both rat and human data. Unbound vs. tota l plasma clearances were obtained for 15 our of 53 drugs and their cor relations between humans and rats were compared. Results. The mean +/- SD of the allometric exponent for the 54 drugs studied is 0.660 +/- 0 .190. The median clearance ratio based on unit body weight is 7.41 and the median exponent ii; 0.645. Excluding two outliers the correlation coefficient of plasma clearance between humans and rats was 0.745 (p < 0.0001). For the 15 drugs, use of unbound plasma clearance approach seems to significantly improve the correlation coefficient compared to total plasma clearance (0.940 vs. 0.841). Conclusions. The present st udy indicates that on average, humans and rats may eliminate extensive ly metabolized drugs at a rate similar to that expected from the allom etric or body surface area relationship of basal metabolic rate betwee n the two species. A simple statistical distribution hypothesis is use d to rationalize the species difference in plasma drug clearance. Rat may serve as an useful animal model to predict (unbound) plasma cleara nce of drugs in humans.