PHARMACOKINETICS OF MICHELLAMINE B, A NAPHTHYLISOQUINOLINE ALKALOID WITH IN-VITRO ACTIVITY AGAINST HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 AND TYPE-2, IN THE MOUSE AND DOG

Michellamine B (MB) is a naturally occurring naphthylisoquinoline alka loid of novel chemical structure with activity against human immunodef iciency virus (HIV) types 1 and 2 in vitro. In conjunction with its pr eclinical evaluation, the plasma pharmacokinetics of MB was characteri zed 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 w eight, the drug exhibited apparent first-order kinetics in both specie s, affording triexponential plasma concentration-time profiles. Treatm ent with doses of 5 to 9 mg/kg provided peak plasma levels within the range that completely inhibits the cytopathic effects of HN upon cultu red human lymphoblastoid cells (50 to 100 mu g/ml) without evidence of toxicity. MB had a biological half-life of 2.8 +/- 0.8 h in mice, wit h 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); howeve r, the terminal-phase contribution to the area under the plasma profil e from time zero to infinity was 44.6% +/- 12.9%. In contrast, the ter minal phase was the primary determinant of drug disposition in dogs, a ccounting for 74.1% +/- 2.8% (n = 3) of the area under the curve. Furt hermore, the systemic duration of MB was significantly longer in the d ogs than in mice, as indicated by mean values of the apparent half-lif e (11.6 +/- 1.2 h), mean residence time (12.3 +/- 1.8 h), and clearanc e (0.50 +/- 0.08 ml/min/kg). However, there was no statistical differe nce 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 a lso treated with a total dose of 97 mg/kg given as a 72-h constant-rat e intravenous infusion, since prolonged systemic exposure to potential ly therapeutic drug concentrations will very likely be required for cl inical anti-HIV effects. Within 4 h after starting the infusion, the p lasma MB concentration exceeded 18 mu g/ml, its reported 50% effective concentration against HIV in vitro, and subsequently increased to 41 mu g/ml at the end of the infusion. There were no clinical or patholog ical indications of toxicity. Whereas the total plasma clearance (0.48 ml/min/kg) was within the range observed for dogs treated by 15-min i nfusion, 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 amo unt 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 basi s of these findings, continued development of MB as a novel lead compo und for the treatment of BTV infection is warranted.