Plasma pharmacokinetics of michellamine B in mice and dogs (Meeting abstract).

Important note: Information in this article was accurate in 1995. The state of the art may have changed since the publication date.

Plasma pharmacokinetics of michellamine B in mice and dogs (Meeting abstract).

Proc Annu Meet Am Assoc Cancer Res; 35:A2520 1994. Unique Identifier : AIDSLINE ICDB/95604205
Supko JG; Malspeis L; Lab. of Pharmaceutical Chemistry, NCI, Frederick, MD 21702

Abstract: Michellamine B (MB; NSC 649324) is a naturally occurring alkaloid of novel chemical structure that exhibits promising in vitro activity against HIV types 1 and 2. In conjunction with its preclinical evaluation as an anti-HIV agent, the plasma pharmacokinetics of MB was characterized in mice at doses of 1.0, 4.7 and 9.5 mg/kg, given by rapid iv injection, and beagle dogs treated by 15 min iv infusion with 4 doses in the range 0.9-17 mg/kg. Drug disposition was triexponential and kinetically linear in both species. In mice, MB had a biological half-life of 2.8 +/- 0.8 hr, a 2.1 +/- 0.3 hr mean residence time and a total plasma clearance of 2.4 +/- 0.5 ml/min/kg (mean +/- SD); however, the area under the plasma profile associated with the terminal phase (AUCz) was only 44.6 +/- 12.9%. In contrast, the terminal phase was the primary determinant of drug disposition in dogs (AUCz = 75.4 +/- 3.5%). Furthermore, the systemic duration of MB was significantly longer, as indicated by the biological half-life (11.3 +/- 1.1 hr), mean residence time (12.6 +/- 1.4 hr) and clearance (0.57 +/- 0.16 ml/min/kg). The apparent volumes of distribution (V1, Vss, Vz) were very similar in the mouse and dog. In a dog given a total dose of 97.0 mg/kg by 72 hr continuous iv infusion, the MB plasma concentration exceeded 20 uM at 4 hr and gradually increased to 49 uM at the end of infusion. The animal showed no indications of toxicity. These studies demonstrate that concentrations of MB, in the range that provided optimal in vitro antiviral effects (EC50 approx 20 uM), can be achieved systemically and are well tolerated by mice and dogs. However, due to its extremely poor oral bioavailability, continuous parenteral administration will most likely be required to sustain therapeutic plasma concentrations.

Keywords: Animal Antiviral Agents/*PHARMACOKINETICS Dogs HIV-1/DRUG EFFECTS HIV-2/DRUG EFFECTS Isoquinolines/*PHARMACOKINETICS Mice Naphthalenes/*PHARMACOKINETICS ABSTRACT
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