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 biophysical model approach to assess biological activity of anthelmintics in light of drug-delivery principles. The relationships between drug absorption and efficacy for a set of structurally disparate anthelmintics were determined in cultures of Haemonchus contortus, a nematode that parasitizes the ruminant gastrointestinal tract. Uptake, parameterized by the permeability coefficient, Pe, was shown to occur by absorption 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/medium partition coefficient, K, was derived from the ratio of drug concentration in the parasite vs the medium at equilibrium. Pe and K values for each anthelmintic were correlated with lipophilicity (as measured by the partition coefficient (PC) in n-octanol/water) and both parameters plateaued at log PC approximately 2.5, with maximum Pe approximately 8 x 10(-4) cm/min and log K < or = 2.0. Absorption kinetics were related to in vitro potency by monitoring motility of H. contortus. The time required to reduce motility by 50% (t* 50) and Pe were used to calculate Cn*, the drug concentration in the parasite at t* 50, as an indicator of intrinsic potency. The quantitative interplay of apparent biological activity expressed as t* 50, dose, and intrinsic potency highlights the important contribution of drug-uptake kinetics.
Drug Delivery Systems Research, Upjohn Laboratories, Upjohn Company, Kalamazoo, MI 49001.
N F
NF
Ho
S M
SM
Sims
T J
TJ
Vidmar
J S
JS
Day
C L
CL
Barsuhn
E M
EM
Thomas
T G
TG
Geary
D P
DP
Thompson
D000042:Absorption; D000818:Animals; D000871:Anthelmintics / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D001692:Biological Transport; D002627:Chemistry, Physical / Q000379:methods; D005260:Female; D006189:Haemonchus / Q000187:drug effects* / Q000378:metabolism*; D007700:Kinetics; D008954:Models, Biological; D008956:Models, Chemical; D013329:Structure-Activity Relationship
D000871:Anthelmintics