Use of a rat model for the simultaneous assessment of pharmacokinetic and pharmacodynamic aspects of bisphosphonate treatment: Application to the study of intravenous 14C‐labeled 1‐hydroxy‐3‐(1‐pyrrolidinyl)‐propylidene‐1,1‐bisphosphonate

Bisphosphonates are drugs that suppress osteoclast‐mediated bone resorption and are used with increasing frequency in the treatment of skeletal disorders. Therapeutic regimens are largely based on pharmacodynamic information because of difficulties in obtaining and interpreting pharmacokinetic data. We describe here the application of a permanently cannulated rat model, previously used in other areas of endocrine research, to the simultaneous study of pharmacokinetic and pharmacodynamic properties of the newly developed bisphosphonate EB‐1053 [1‐hydroxy‐3‐(1‐pyrrolidinyl)propylidene‐1,1‐bisphosphonate]. Two groups of five rats each received daily intravenous injections of [14C]EB‐1053 (0.025 and 0.1 mg/day, respectively); a third group (n = 7) received only normal saline injections and served as control. Treatment was given for at least 20 days. A fourth group (n = 3) received IV injections of the bisphosphonate on three separate occasions. Following IV administration, EB‐1053 was rapidly cleared from the circulation. Urinary excretion of radioactivity reached about 55% of the daily administered dose within 48 h and remained at this level during the whole treatment period, indicating continuing retention of the bisphosphonate. Bone resorption, assessed biochemically as the hydroxyproline to creatinine ratio in urine, was suppressed effectively with both doses used. Suppression reached a maximum around day 4 and remained at the same level until the end of treatment. Accumulation of the bisphosphonate in the skeleton was therefore not associated with a cumulative effect on bone resorption. This strongly suggests that in treatment planning a distinction should be made 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 other issues of bisphosphonate pharmacology, such as sequential changes in biochemical parameters of bone metabolism in plasma and urine of the same animal, which are necessary for the planning of long‐term therapy with uninterrupted administration of these compounds.