USE OF A RAT MODEL FOR THE SIMULTANEOUS ASSESSMENT OF PHARMACOKINETICAND PHARMACODYNAMIC ASPECTS OF BISPHOSPHONATE TREATMENT - APPLICATIONTO THE STUDY OF INTRAVENOUS C-14-LABELED -3-(1-PYRROLIDINYL)-PROPYLIDENE-1,1-BISPHOSPHONATE

Bisphosphonates are drugs that suppress osteoclast-mediated bone resor ption and are used with increasing frequency in the treatment of skele tal disorders. Therapeutic regimens are largely based on pharmacodynam ic information because of difficulties in obtaining and interpreting p harmacokinetic data. We describe here the application of a permanently cannulated rat model, previously used in other areas of endocrine res earch, to the simultaneous study of pharmacokinetic and pharmacodynami c properties of the newly developed bisphosphonate EB-1053 3-(1-pyrrol idinyl)propylidene-1,1-bisphosphonate]. Two groups of five rats each r eceived daily intravenous injections of [C-14]EB-1053 (0.025 and 0.1 m g/day, respectively); a third group (n = 7) received only normal salin e injections and served as control. Treatment was given for at least 2 0 days. A fourth group (n = 3) received IV injections of the bisphosph onate on three separate occasions. Following IV administration, EB-105 3 was rapidly cleared from the circulation. Urinary excretion of radio activity reached about 55% of the daily administered dose within 48 h and remained at this level during the whole treatment period, indicati ng continuing retention of the bisphosphonate. Bone resorption, assess ed biochemically as the hydroxyproline to creatinine ratio in urine, w as suppressed effectively with both doses used. Suppression reached a maximum around day 4 and remained at the same level until the end of t reatment. Accumulation of the bisphosphonate in the skeleton was there fore not associated with a cumulative effect on bone resorption. This strongly suggests that in treatment planning a distinction should be m ade between surface-bound and hence biologically active bisphosphonate from the drug which is incorporated in bone during bone turnover. The rat model used in these studies may also allow the examination of oth er issues of bisphosphonate pharmacology, such as sequential changes i n biochemical parameters of bone metabolism in plasma and urine of the same animal, which are necessary for the planning of long-term therap y with uninterrupted administration of these compounds.