Being classified as a World Health Organization class II analgesic, the synthetic opioid tilidine is used for treatment of moderate or strong pain or for long-term treatment of patients with chronic pain [1–3]. In Germany, it is marketed as a fixed combination of tilidine and the opioid antagonist naloxone to prevent abuse. Tilidine is a classical prodrug, with the therapeutic activity being elicited by its oxidative metabolite, nortilidine [4, 5], which easily penetrates the blood–brain barrier and binds to the µ-opioid receptor as an agonist with a 100-fold higher µ-receptor affinity than tilidine itself [4, 6]. Recently, it was demonstrated that tilidine is a substrate of cytochrome P450 (CYP) isozymes, especially CYP3A4 and CYP2C19 . Tilidine undergoes a so-called sequential metabolism; two-thirds of an administered dose is converted to nortilidine, while about 50% of the formed nortilidine is further metabolized to bisnortilidine before leaving the metabolizing organ . In a recently published study, the simultaneous inhibition of CYP3A4 and CYP2C19 by voriconazole resulted in a 20-fold increase of tilidine exposure . However, the anticipated reduction of nortilidine formation did not result in a reduced exposure of the active metabolite, nortilidine; instead, a threefold increase was observed. This was explained by the inhibition of both metabolic steps of the sequential tilidine metabolism by voriconazole .
To date, it is unknown which enzyme(s) are involved in the second metabolic step (formation of bisnortilidine from nortilidine). From the data of the voriconazole interaction study, it can be suggested that at least CYP3A4 and CYP2C19 are involved . The relative contribution of both enzymes to the sequential metabolism is unknown, nor is the relevance of the known CYP2C19 genetic polymorphism. The novel described CYP2C19 gene variant CYP2C19*17 causes ultrarapid drug metabolism [10, 11], which is in contrast to the *2 or *3 variants that result in impaired drug metabolism . This ultrarapid drug metabolism is caused by enhancement of the expression of CYP2C19 . Therefore, these mutations in the CYP2C19 gene might have an impact on tilidine sequential metabolism, resulting in large interindividual variability. The contribution of CYP3A4 to this sequential metabolism is also of interest and can be quantified using a potent CYP3A4 inhibitor, such as ritonavir [13, 14]. Hence, in this randomized, placebo-controlled, double-blind, cross-over study we investigated the contribution of CYP3A4 and CYP2C19 to the overall metabolism of tilidine in humans by using ritonavir to inhibit CYP3A4 potently in subjects stratified according to their CYP2C19 genotype (poor and ultrarapid metabolizers).