Inhibition of ethinyloestradiol and tolbutamide metabolism by quinoline derivatives in vitro.

The effects of the quinoline derivatives amodiaquine (AQ), chloroquine (CQ), mefloquine (MQ), primaquine (PQ), quinine (Q) and quinidine (QD) on in vitro hepatic metabolism has been studied using as substrates ethinyloestradiol (EE2) and tolbutamide (TOL). The 2-hydroxylation of EE2 and the hydroxylation of TOL were determined in the presence of variable concentrations of each compound. MQ, PQ, AQ and Q significantly inhibited EE2 metabolism at each of the concentrations studied (0.1, 0.2 and 0.5 mM) as shown by an increase in the percentage of unmetabolised EE2. QD significantly inhibited metabolism at 0.2 and 0.5 mM but CQ was without effect. In terms of recovery of 2-OHEE2, PQ was the most potent inhibitor. At an inhibitor concentration of 0.5 mM the order of potency was PQ greater than or equal to MQ greater than or equal to Q greater than or equal to QD greater than or equal to AQ greater than or equal to CQ. TOL hydroxylase activity in control microsomes was 1.52 +/- 0.33 nmol. min-1 X mg protein-1. The order of potency of the inhibitors (0.5 mM) was PQ greater than or equal to MQ greater than or equal to Q greater than or equal to QD greater than or equal to AQ greater than or equal to CQ. These data provide further evidence of the inhibitory potential of some of the quinoline derivatives. PQ, MQ, and to a lesser extent Q produce the most marked inhibitory effects. QD and AQ are of intermediate potency and CQ is essentially non-inhibitory.