Allometric scaling of xenobiotic clearance: Uncertainty versus universality

Abstract

Statistical analysis and Monte Carlo simulation were used to characterize uncertainty in the allometric exponent (b) of xenobiotic clearance (CL). CL values for 115 xenobiotics were from published studies in which at least 3 species were used for the purpose of interspecies comparison of pharmacokinetics. The b value for each xenobiotic was calculated along with its confidence interval (CI). For 24 xenobiotics (21%), there was no correlation between log CL and log body weight. For the other 91 cases, the mean±standard deviation of the b values was 0.74±0.16; range: 0.29 to 1.2. Most (81%) of these individual b values did not differ from either 0.67 or 0.75 at P=0.05. When CL values for the subset of 91 substances were normalized to a common body weight coefficient (a), the b value for the 460 adjusted CL values was 0.74; the 99% CI was 0.71 to 0.76, which excluded 0.67. Monte Carlo simulation indicated that the wide range of observed b values could have resulted from random variability in CL values determined in a limited number of species, even though the underlying b value was 0.75. From the normalized CL values, 4 xenobiotic subgroups were examined: those that were (i) protein, and those that were (ii) eliminated mainly by renal excretion, (iii) by metabolism, or (iv) by renal excretion and metabolism combined. All subgroups except (ii) showed a b value not different from 0.75. The b value for the renal excretion subgroup (21 xenobiotics, 105 CL values) was 0.65, which differed from 0.75 but not from 0.67.