Pharmacokinetics of the anti-HIV Bicyclam SID791 (JM3100) in Rabbits, as Determined by both Analytical and Bio-Assay Methods

Abstract

The serum levels of the bicyclam derivative 1,1′-[1,4-phenylenebis(methylene)]-bis-1,4,8,11-etraazacyclotetradecane octahydrochloride dihydrate [SID791 (JM3100)], a potent inhibitor of HIV replication (De Clercq et al., 1994) were determined in rabbits using two different methods. A method based on the UV-absorption of the Cu-complex of SID791 was used to analyse by HPLC the serum drug concentrations, and an antiviral activity bio-assay was performed to investigate whether the drug in the rabbit serum was in an available active form. After subcutaneous (sc) administration of SID791 to rabbits at 25 mg kg−1 of body weight, the compound was cleared from the serum in a bi-exponential manner (β1-half-lives: 67 and 69 min; β2-half-lives: 320 and 245 min; distribution volumes: 0.40 and 0.37 I; total body clearance: 0.30 and 0.29 I h−1; and AUC: 83.3 and 86.2 h μg ml−1, as determined by HPLC and bio-assay, respectively). Thus, very similar kinetic parameters were noted if serum drug concentrations were determined by HPLC analysis or bio-assay, suggesting that in the rabbit serum the drug is present as an antiviral active agent.