Studies on the Pharmacology of Methaqualone: Induction of Mammalian Hepatic δ-Aminolevulinic Acid Synthetase

Abstract

Summary

Methaqualone, a highly abused quinazoline derivative with demonstrated therapeutic efficacy, significantly stimulates the activity of hepatic δ-aminolevulinic acid (ALA) synthetase, the first and rate-limiting enzyme in heme biosynthesis in adult mammals. In adult rats, methaqualone produces a rapid and sustained increase in hepatic ALA synthetase activity in doses which correspond in man to both therapeutic (5-10 mg/kg) or overdose (25-50 mg/kg) levels. The major increase in enzyme activity occurs within 12 hr after drug treatment. Elevated enzyme levels are sustained for at least 48 hr after administration of a single dose and for several days after daily ingestion of the drug for 1 wk. The increase in ALA synthetase activity produced by methaqualone can be prevented by simutaneous administration of hemin or by pretreatment with cycloheximide and cannot be demonstrated in vitro. This study represents the first demonstration of stimulation of mammalian ALA synthetase activity by a quinazoline derivative. The mechanism of action of methaqualone appears to be by induction of enzyme synthesis. Although single therapeutic dose levels (5-10 mg/kg/day) probably do not induce the enzyme to a significant extent as to warrant contraindication of this drug in prescribed usage, ingestion of abusive doses may significantly alter hepatic heme metabolism. These studies suggest, however, that quinazoline derivatives may serve as useful pharmacologic tools for the further investigation of the regulation of mammalian heme synthesis.