Pharmacokinetic characteristics of the new
xanthine bronchodilators,
enprofylline and
1-methyl-3-propylxanthine (MPX), were investigated in mice, rats, guinea-pigs, rabbits and dogs. The possibility of an interspecies pharmacokinetic scale was also evaluated. The concentration of these two drugs in plasma and urine was determined by HPLC. Pharmacokinetic parameters were calculated using model-independent methods. The disappearance curves of the two drugs from plasma varied markedly among animal species. Interspecies differences in the
plasma protein binding of each
drug were observed for all animals in the study. Differences in the biotransformation of
enprofylline and MPX were also confirmed among the various animal species:
enprofylline is mainly excreted in an unchanged form in urine while MPX follows a non-renal route of elimination. In all animals, the renal clearance for
enprofylline was greater than the glomerular filtration rate, indicating active tubular secretion. Significant allometric relationships were seen between the values of total body clearance and steady state volume of distribution for both total and unbound
enprofylline and species
body weight, but similar correlations could not be recognized for MPX. Renal clearance of
enprofylline was also closely correlated with species
body weight, suggesting no interspecies difference with relation to affinity and/or capacity for the active tubular secretion mechanism of
enprofylline. Our findings suggest that
xanthine derivatives, including
enprofylline, are mainly eliminated via the kidney, and an estimate of the basic pharmacokinetics in man can be obtained from data in experimental animals.