Pharmacokinetics of UC 38-related congeners demonstrating in vitro activity against native and mutant strains of HIV (Meeting abstract).

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

Pharmacokinetics of UC 38-related congeners demonstrating in vitro activity against native and mutant strains of HIV (Meeting abstract).

Proc Annu Meet Am Assoc Cancer Res; 36:A2173 1995. Unique Identifier : AIDSLINE ICDB/95609948
Stinson SF; Schultz RJ; Malspeis L; Laboratory of Pharmaceutical Chemistry, DTP, DCT, NCI, FCRDC,; Frederick, MD 21702

Abstract: UC-38 is a non-nucleoside reverse transcriptase inhibitor with potent anti-HIV activity in the NCI's anti-HIV drug screen. Due to rapid in vivo clearance of UC-38, pharmacokinetic and metabolic considerations were used to design congeners with resistance to metabolism, high oral bioavailability and potent anti-HIV activity. Compounds with good activity against native and mutant strains of HIV were initially screened in a mouse liver homogenate assay; IV and oral murine pharmacokinetic studies were conducted on compounds with the greatest resistance to in vitro metabolism. The primary structural determinants of in vitro metabolism, in vivo plasma clearance and oral bioavailability were characterized. Of the compounds tested, NSC 645129, a molecule containing t-butoxime and furylthioamide moieties, had the highest plasma concentrations following po administration and the greatest oral bioavailability. A dose of 80 umol/kg (28 mg/kg) was given to 3 dogs by 1 hr IV infusion. Plasma concentrations exhibited triexponential behavior. The mean total body plasma clearance was 18.9 mL/min/kg. The mean total body volume of distribution (6.6 L/kg) suggests that the compound was highly distributed to deep tissue compartments. Crossover studies with 300 umol/kg (105 mg/kg) administered po afforded bioavailabilities of 85-90%. Plasma concentrations 24 hr after administration (4-8 uM), were in excess of those required for inhibition of HIV induced cytopathic effects in vitro.

Keywords: Administration, Oral Animal Antiviral Agents/PHARMACOLOGY/*PHARMACOKINETICS Biological Availability Biotransformation Dogs Dose-Response Relationship, Drug HIV/*DRUG EFFECTS/GENETICS Infusions, Intravenous Metabolic Clearance Rate Mutation RNA-Directed DNA Polymerase/*ANTAGONISTS & INHIB Structure-Activity Relationship ABSTRACT
951230
M95C3213

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