Accumulation of bisphosphonates in the aorta and some other tissues of healthy and atherosclerotic rabbits.

Clodronate, etidronate, and pamidronate are highly hydrophilic bisphosphonates used for the treatment of bone resorption and hypercalcemia. They also inhibit the development of experimental atherosclerosis without influencing serum cholesterol level. We studied the distribution and the accumulation of the carbon 14-labeled bisphosphonates in the aorta and some other tissues of healthy rabbits and in rabbits with diet-induced atherosclerosis. After intravenous injection, clodronate and pamidronate disappeared from circulation more slowly in atherosclerotic than in healthy rabbits, and the drug concentrations in the peripheral tissues were generally lower in atherosclerotic than in healthy animals. At 24 hours after dosing in healthy rabbits, the mean aorta to plasma ratios of clodronate, etidronate, and pamidronate were, respectively, 2.4 to 2.8, 2.4 to 4.0, and 8.6 to 10. The corresponding ratios in atherosclerotic rabbits were, respectively, 13 to 22, 1.5 to 2.2, and 13 to 24. Seven days after the injection the mean clodronate concentration in the aortas of healthy rabbits was 0.5% to 0.9% of the dose given per tissue weight, and the concentration in those of atherosclerotic animals was 3.8% to 5.2% of the dose given per tissue weight. The results indicate that hydrophilic bisphosphonates, known to inhibit the atherogenesis, concentrate markedly in the aortas of healthy and atherosclerotic rabbits.