Mode of administration-dependent pharmacokinetics of bisphosphonates and bioavailability determination.
We investigated the influence of mode of administration on the pharmacokinetics of a clinically used bisphosphonate, pamidronate, and of suberoylbisphosphonate (SuBP), a novel bisacylphosphonate of the P-CO-(C)(n)-CO-P type, in rats. Serum drug levels and tissue disposition were determined following administration of the drugs by different modes: intravenous bolus (iso-osmotic and hypo-osmotic solutions), continuous intravenous infusion, and peroral administration. Results of the study indicate that the disposition of the bisphosphonates in soft tissue (liver, kidney and spleen) was dependent on route and rate of drug administration, and on the osmoticity of the vehicle. Consequently, main pharmacokinetic parameters (AUC, CL, and V(ss)) were influenced by the mode of drug administration, precluding accurate determination of bioavailability from AUC values. On the other hand, bone and urine bisphosphonate accumulation were considerably less dependent on mode of administration, and, therefore, are recommended for bioavailability calculation.
Hoffman
A
A
Department of Pharmaceutics, School of Pharmacy, The Hebrew University of Jerusalem, P.O. Box 12065, 91120, Jerusalem, Israel. ahoffman@cc.huji.ac.il
Stepensky
D
D
Ezra
A
A
Van Gelder
J M
JM
Golomb
G
G
D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001682:Biological Availability; D004164:Diphosphonates / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006207:Half-Life; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D007408:Intestinal Absorption; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D008657:Metabolic Clearance Rate; D000077268:Pamidronate; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley
D000894:Anti-Inflammatory Agents, Non-Steroidal; D004164:Diphosphonates; C074668:suberoylbisphosphonic acid; D000077268:Pamidronate