The Metabolic Fate of the Anti-HIV Active Drug Carrier Succinylated Human Serum Albumin after Intravenous Administration in Rats

Abstract

The pharmacokinetics and metabolic fate of the intrinsically active (anti-HIV) drug carrier succinylated human serum albumin (Suc-HSA) was studied in rats. Suc-HSA was prepared by derivatizing HSA with 1,4-[¹⁴C]-succinic anhydride, a modification by which all available εNH₂-groups in HSA were converted into carboxylic groups.

After iv injections of 0.3, 1.0, 3.0 and 10.0 mg/kg in freely moving rats, Suc-HSA showed a dose dependent elimination pattern, indicating a saturable elimination pathway. The Michaelis-Menten parameters V_max and K_m were 98.7 μg.min⁻¹.kg⁻¹ and 8.5 μg.ml⁻¹ respectively. The kinetics of Suc-HSA was influenced by anaesthesia. In anaesthetised animals, V_max and K_m were found to be 26.9 μg.min⁻¹.kg⁻¹ and 0.26 μg.ml⁻¹, respectively. This implies an intrinsic clearance of 100ml.min⁻¹.kg⁻¹, which is about 10-fold higher as compared to 12 ml.min⁻¹.kg⁻¹ in freely moving animals.

Intravenous administration of a sub-saturable dose of 3.0mg.kg⁻¹1,4-[¹⁴C]-Suc-HSA to freely moving rats resulted in a biphasic elimination with an initial t1/2 of 20 min and a terminal t1/2 of 40 hrs. Excretion of metabolites in urine and faeces lasted for at least 48 hours. About 70% of the radioactive dose was excreted in urine, whereas maximally 2% was detected in faeces. Suc-HSA was degraded to its individual amino acids including succinylated lysine (the only radioactive product formed). Succinylated lysine was not further metabolised and mainly excreted via the urine. Immunohistochemical staining showed that even after 48 hrs Suc-HSA could be detected in livers. Together with the urinary excretion patterns, this points to a gradual degradation of Suc-HSA.

Key Words:

• drug targeting
• HIV-1
• metabolism
• pharmacokinetics
• polyanion
• succinylated albumin