Pharmacogenetic determinants of codeine induction by rifampin: the impact on codeine's respiratory, psychomotor and miotic effects

Abstract

Our objective was to examine the effect of rifampin on codeine's pharmacodynamics and pharmacokinetics in extensive (EMs) and poor (PMs) metabolizers of debrisoquin. Fifteen healthy, nonsmoking males, 9 EMs and 6 PMs of debrisoquin, received codeine (120 mg) before and after rifampin (600 mg/d) for 3 weeks. The effects of codeine on respiration, pupil diameter and psychomotor performance were measured before codeine administration and during each study day. The pharmacokinetics of codeine were determined from the respective plasma and urine concentrations. Before the administration of rifampin, the pharmacodynamic effects of codeine were more prominent in the EMs (P < .01). Rifampin significantly enhanced codeine oral clearance by increasing its metabolic clearances through N-demethylation and glucuronidation in both phenotypes, but its O-demethylation was induced only in EMs. Relative to base-line values, codeine N-demethylation was induced to a greater extent, resulting in a marked reduction in the plasma concentrations of codeine and codeine metabolites and elevated plasma concentrations of norcodeine, norcodeine-glucuronide, and normorphine. The reduction in morphine plasma concentration was associated in the EMs with a significant attenuation of codeine's respiratory and psychomotor effects, whereas its miotic effect was unaltered. In PMs, codeine's respiratory and psychomotor effects were unaltered by rifampin, but its pupillary effect was reduced. Codeine O-demethylation to produce morphine can be significantly induced by rifampin, but this induction is phenotypically determined. However, because (relative to base-line values) rifampin enhanced codeine N-demethylation more than codeine O-demethylation, morphine plasma concentrations were reduced-and hence codeine's pharmacodynamic effects were attenuated-in EMs of debrisoquin.