THEORETICAL PERSPECTIVES ON ANTHELMINTIC DRUG DISCOVERY - INTERPLAY OF TRANSPORT KINETICS, PHYSICOCHEMICAL PROPERTIES, AND IN-VITRO ACTIVITY OF ANTHELMINTIC DRUGS

This multidisciplinary study demonstrates the utility of the biophysic al model approach to assess biological activity of anthelmintics in li ght of drug-delivery principles. The relationships between drug absorp tion and efficacy for a set of structurally disparate anthelmintics we re determined in cultures of Haemonchus contortus, a nematode that par asitizes the ruminant gastrointestinal tract. Uptake, parameterized by the permeability coefficient, P theta, was shown to occur by absorpti on across the cuticle. Rates of drug appearance in nematode carcasses paralleled rates of drug disappearance from the medium, and absorption reached an apparent equilibrium within a few hours. The parasite/medi um partition coefficient, K, was derived from the ratio of drug concen tration in the parasite vs the medium at equilibrium. P-theta and K va lues for each anthelmintic were correlated with lipophilicity (as meas ured by the partition coefficient (PC) in n-octanol/water) and both pa rameters plateaued at log PC approximate to 2.5, with maximum P(theta) approximate to 8 X 10(-4) cm/min and log K less than or equal to 2.0. Absorption kinetics were related to in vitro potency by monitoring mot ility of H. contortus. The time required to reduce motility by 50% (t (50)) and P theta were used to calculate C-n, the drug concentration in the parasite at t(50), as an indicator of intrinsic potency, The q uantitative interplay of apparent biological activity expressed as t( 15), dose, and intrinsic potency highlights the important contribution of drug-uptake kinetics.