Tramadol in Japanese Population: the Relative Contribution of M1 Metabolite as Assessed by <i>CYP</i>2<i>D</i>6</i>*10 Genotype

Abstract

Several preclinical and clinical studies suggested that tramadol has a multi-mechanistic analgesic action. Upon <i>in vitro</i> evaluation, tramadol parent drug was determined to have only very weak affinity for opioid receptors. Metabolism <i>via</i> CYP2D6, though, yields the <i>O</i>-desmethyl metabolite (M1), which has much greater opioid receptor affinity. In tests in animals and human volunteers, tramadol’s analgesic effect is only partially blocked by the opioid antagonist naloxone. Yet the contribution of parent drug to analgesia is still debated. Observance of good analgesic response to tramadol in Japanese and other Asian populations that express the <i>CYP</i>2<i>D</i>6</i>*10 genotype suggests that parent drug accounts for the majority of tramadol’s analgesic effect in most clinical settings. Understanding of tramadol’s multi-mechanistic action continues to form the basis for understanding its clinical attributes

Tramadol toxicity in a cat: case report and literature review of serotonin syndrome

“…30 Dehydration was noted on presentation to the referring veterinarian, which may have decreased the rate of drug absorption from the gastrointestinal system and slowed elimination via the kidneys. Polymorphism in the CYP 450 enzyme system affects the metabolism and clearance of tramadol in humans, 23 and may also exist in cats. 24 The half-life of tramadol is extended in healthy humans over 75 years of age 28 and this may have been a factor in this geriatric cat.…”

“…21,22 In humans, polymorphism in the CYP 450 enzyme system affects the metabolism and clearance of tramadol. 23 As yet, CYP 450 isoforms have not been well characterised in dogs or cats. 24 In one study, overall CYP activities in cat liver microsomes were lower than in those from dogs or humans, except for CYP2B.…”

Pharmacokinetics of Tramadol and Celecoxib in Japanese and Caucasian Subjects Following Administration of Co-Crystal of Tramadol-Celecoxib (CTC): A Randomised, Open-Label Study

“…Differences in CYP3A4 expression levels between Japanese and Caucasian cohorts have also been reported [27]. CYP2D6*10 is associated with a low conversion of tramadol to M1 and is thought to have a high incidence in Japanese populations, occurring in approximately 20–45% of individuals [28]. In the present study, one subject (in the Caucasian cohort) appeared to have low M1/tramadol ratios and was therefore considered to possibly be a poor CYP2D6 metaboliser (although genotyping did not form part of the study).…”