Pharmacokinetics of Buprenorphine Hydrochloride (BN HCl). (1). Absorption, Distribution, Metabolism and Excretion after Percutaneous (TSN-09: BN HCl Containing Tape Application) or Subcutaneous Administration of BN HCl in Rats.

Abstract

The Pharmacokinetics of 3H-BN·HCl in male rats was studied after a single percutaneous (3HTSN-09 : 3H-BN·HCl containing tape) or subcutaneous administration of 3H-BN·HCl. 1. The radioactivity level in blood reached the Cmax at 21.6 hr after a single percutaneous administration, then decreased with the t1/2 of 4.8 days, and the unchanged drug concentration in plasma reached the Cmax at 8 hr after dosing. When 3H-BN·HC1 was administered percutaneously as a tape formulation (3H-TSN-09) at the dosage of 20, 40 or 80μg of 3H-BN·HCl/animal, the Cmax and AUC0-∞ value increased in proportion to the administered dose. From the AUC0-∞ values in percutaneous and subcutaneous administration, the absorption ratio of percutaneous administration was calculated to account for about 14% of dose. The Tmax of each dose was observed at around the end of application period, indicating the absorption of 3H-BN·HCl through skin to continue during application period. 2. When 3H-TSN-09 was applied to the shaved area skin in rats, the whole body autoradiogram showed high level of radioactivity of the application site of the skin, low level of radioactivity in the gastro-intestinal contents and little level of radioactivity in most other tissues. 3. Within 168 hr after a single percutaneous administration, 1.0 and 8.2% of dose was excreted into urine and feces, respectively. 4. The binding of BN·HCl to plasma protein varied from 88.9 to 97.4% in rat, dog or human. BN·HCl bound to human serum albumin, γ-globulin and α1-acid glycoprotein and their binding ratios were 65.5, 41.5 and 84.9%, respectively. 5. After a single percutaneous administration of 3H-BN·HCl to rats, two metabolites, RP1 and RP2 were detected in plasma. The structures of RP1 and RP2 were identified as norbuprenorphine-glucuronide and BN-glucuronide, respectively. These two metabolites were also found in rat plasma after a single subcutaneous administration. So it was considered that the metabolic pathway of BN·HCl might be the same in both administration routes.