Pharmacokinetics of michellamine B, a naphthylisoquinoline alkaloid with in vitro activity against human immunodeficiency virus types 1 and 2, in the mouse and dog

Abstract

Michellamine B (MB) is a naturally occurring naphthylisoquinoline alkaloid of novel chemical structure with activity against human immunodeficiency virus (HIV) types 1 and 2 in vitro. In conjunction with its preclinical evaluation, the plasma pharmacokinetics of MB was characterized in mice and dogs treated by intravenous infusions of 1- and 15-min durations, respectively. At doses ranging from 1 to 9 mg/kg of body weight, the drug exhibited apparent first-order kinetics in both species, affording triexponential plasma concentration-time profiles. Treatment with doses of 5 to 9 mg/kg provided peak plasma levels within the range that completely inhibits the cytopathic effects of HIV upon cultured human lymphoblastoid cells (50 to 100 micrograms/ml) without evidence of toxicity. MB had a biological half-life of 2.8 +/- 0.8 h in mice, with a mean residence time of 2.1 +/- 0.3 h, and a total plasma clearance of 2.4 +/- 0.5 ml/min/kg (mean +/- standard deviation; n = 3); however, the terminal-phase contribution to the area under the plasma profile from time zero to infinity was 44.6% +/- 12.9%. In contrast, the terminal phase was the primary determinant of drug disposition in dogs, accounting for 74.1% +/- 2.8% (n = 3) of the area under the curve. Furthermore, the systemic duration of MB was significantly longer in the dogs than in mice, as indicated by mean values of the apparent half-life (11.6 +/- 1.2 h), mean residence time (12.3 +/- 1.8 h), and clearance (0.50 +/- 0.08 ml/min/kg). However, there were no statistical difference between its apparent volume of distribution in the mice (0.60 +/- 0.08 liters/kg) and dogs (0.50 +/- 0.07 liters/kg). A single dog was also treated with a total dose of 97 mg/kg given as a 72-h constant-rate intravenous infusion, since prolonged systemic exposure to potentially therapeutic drug concentrations will very likely be required for clinical anti-HIV effects. Within 4 h after starting the infusion, the plasma MB concentration exceeded 18 micrograms/ml, it reported 50% effective concentration against HIV in vitro, and subsequently increased to 41 micrograms/ml at the end of the infusion. There were no clinical or pathological indications of toxicity. Whereas the total plasma clearance (0.48 ml/min/kg) was within the range observed for dogs treated by 15-min infusion, extension of the postinfusion sampling period from 24 h to 4 days facilitated better definition of the terminal exponential phase, yielding a value of 25.6 h for the biological half-life of MB. The amount of drug excreted by dogs unchanged in the urine ranged from 3.7 to 11.1% of the administered dose. Thus, the major pathways by which the drug is eliminated from the body remain to be identified. On the basis of these findings, continued development of MB as a novel lead compound for the treatment of HIV infection is warranted.