In vitro effects of quinoline derivatives on cytochrome P-450 and aminopyrine N-demethylase activity in rat hepatic microsomes.

A series of quinoline drugs was evaluated for the ability to inhibit rat liver microsomal aminopyrine N-demethylase (APDM) activity in vitro. Quinine was found to be a quite potent inhibitor of APDM from control rat liver (I50 = 0.061 mM) but was only approximately half as potent against APDM from phenobarbitone-induced rat liver (I50 = 0.14 mM). Primaquine and amodiaquine were also relatively potent inhibitors of these activities, but quinidine and chloroquine were essentially non-inhibitory, especially against control-type APDM. Primaquine and quinine elicited characteristic type II optical difference spectra with oxidised cytochrome P-450 from both types of microsomes whereas chloroquine and quinidine were type IIb ligands for cytochrome P-450 in phenobarbitone-induced microsomal fractions. Good correlations were obtained for the logarithmic relationship between binding affinity (Ks) and inhibition potency (I50), as well as the logarithmic relationship between efficiency of binding (delta Amax/Ks) and inhibition. These findings suggest that the capacity of quinoline antimalarials, and similar drugs, to inhibit microsomal APDM activity is related to the affinity of the type II spectral binding interaction between the drug and oxidised cytochrome P-450.