CYP2D6 polymorphism, tramadol pharmacokinetics and pupillary response

Abstract

Dear Professor Dahlqvist, We read with interest the article by Fliegert et al. published online on May 20 that describes pupillometry as an evaluation tool for pharmacodynamic profiling [1]. We have previously studied the pharmacokinetics of (R,S)-(±)tramadol and (±)-O-demethyltramadol (M1) in relationship to drug-induced miosis, as measured by infrared pupillometry in 21 young healthy volunteers comprising three equally sized groups of CYP2D6 EMs, heterozygous EMs, and PMs [2]. Our data differ from those of Fliegert et al. in that both pharmacokinetics and pharmacodynamics of tramadol are genotype-dependent in the groups of heterozygous and homozygous EMs (Fig. 1). We have analysed our data in relation to genotype in order to uncover correlations between pharmacokinetic parameters of tramadol and M1 with pupillary response. As shown in Fig. 1, the plasma levels of the parent compound in heterozygous EMs are, at all sampling intervals, lower and the production of M1 is delayed, leading to a shift to the right of the M1 plasma concentration–time curve in comparison with homozygous EM subjects. Also, pupillary response differed considerably between homozygous and heterozygous EMs. The mean maximal effect in homozygous EMs occurred at 4 h post dose, in heterozygous EMs at 12 h. In contrast to Fliegert et al., we also observed a small miotic action of the drug in the PM group using static pupillometry. Significant negative correlations (Spearman’s test) between both tramadol Cmax and AUC0–24 vs Emax (rs= −0.39 and −0.51, respectively; p<0.05) and AUC0–24 vs area under the effect–time curve (AUD0–12) (rs=−0.41; p<0.05) were observed. Higher and positive correlations between both the M1 Cmax and AUC0–24 vs Emax (rs=0.59 and 0.55, respectively; p<0.01) and vs AUD0–12 (rs=0.55 and 0.52, respectively; p<0.01) were observed. The correlations of pharmacokinetic parameters of M1 vs pupillary effect were thus somewhat stronger than the respective values for the parent compound, but we found the strongest correlation of metabolic ratio (concentration of tramadol/concentration of M1) at all sampling intervals (2.5–24 h post dose) vs. the effects (rs range 0.85–0.89; p<0.01). This presumably means that the parent compound itself possesses a minor miotic action, which is observable in healthy volunteers. We have observed a longer time to maximal miosis in heterozygous subjects than in homozygous ones. Fliegert et al. reported that the time to maximal effect was 4–10 h for the mixed homozygous and heterozygous EMs and speculated that it was be due to delayed transfer of M1 through the blood–brain barrier. Based on our data, the pharmacokinetic differences between homozygotes and heterozygotes could be the reason for this observation. In our opinion, it is necessary to consider heterozygous and homozygous EMs as two separate groups when assessing the pharmacokinetic and/or pharmacodynamic parameters of tramadol. Moreover, in reality, there exists no subject with a mixed homozygous and heterozygous EM genotype, and heterozygous and homozygous EM subjects in European populations represent groups that account for approximately 40% and 50% of persons, respectively. O. Slanař (*) . J. R. Idle . F. Perlik Clinical Pharmacology Unit, Institute of Pharmacology, First Faculty of Medicine, Charles University, Na Bojisti 1, Praha 2, 120 00, Czech Republic e-mail: oslan@lf1.cuni.cz Tel.: +420-2-24964135 Fax: +420-2-24964133