THE PHARMACOKINETICS AND METABOLISM OF HUMAN RELAXINS IN RHESUS-MONKEYS

Two forms of chemically synthesized human relaxin (hRlx and hRlx-2) were administered as 88-mu-g/kg intravenous bolus doses to pregnant and nonpregnant rhesus monkeys. No significant differences in pharmacokinetics were observed between pregnant and nonpregnant animals for either form of relaxin; however, clearance of hRlx (3.1-3.4 ml/min/kg) was significantly slower than clearance of hRlx-2 (6.2-6.5 ml/min/kg) in both pregnant and nonpregnant animals. Although the terminal half-lives for hRlx and hRlx-2 were similar (148-157 min), the initial and steady-state volumes of distribution were somewhat larger for hRlx-2 (71-85 and 398-418 ml/kg, respectively) than for hRlx (61-65 and 294-319 ml/kg, respectively). The metabolism of hRlx-2 was also investigated in pregnant and nonpregnant rhesus monkeys after iv bolus (0.44 mg/kg) or 60-min infusion (1.1 mg/kg) administration. Fast atom bombardment mass spectral analysis of the relaxin immunoreactivity isolated from the plasma indicated that hRlx-2 was partially degraded by removal of amino acids from the C terminus of the B chain. The percentage of intact material declined over a 60-min time course. At 60 min post-dose, intact hRlx-2 was approximately 46-64% of the detected material. Degraded forms representing loss of one and four amino acids (hRlx) from the C terminus of the B chain were approximately 11-13 and approximately 19-34% of the detectable material, respectively.