Impact of fraction unbound, CYP3A, and CYP2D6 in vivo activities, and other potential covariates to the clearance of tramadol enantiomers in patients with neuropathic pain

• Published in: Fundamental & clinical pharmacology 2016-04, Vol.30 (2), p.153-161
• Main Authors: de Moraes, Natália V., Lauretti, Gabriela R., Coelho, Eduardo B., Godoy, Ana Leonor P. C., Neves, Daniel V., Lanchote, Vera L.
• Format: Article
• Language: English
• Subjects: Adult; Analgesics, Opioid - pharmacokinetics; Analgesics, Opioid - therapeutic use; clearance; CYP2B6; CYP2D6; CYP3A; Cytochrome P-450 CYP2D6 - metabolism; Cytochrome P-450 CYP3A - metabolism; Female; fraction unbound; Genotype; Humans; Male; Neuralgia - drug therapy; Neuralgia - metabolism; Stereoisomerism; tramadol; Tramadol - pharmacokinetics; Tramadol - therapeutic use
• ISSN: 0767-3981; 1472-8206
• DOI: 10.1111/fcp.12168

The pharmacokinetics of tramadol is characterized by a large interindividual variability, which is partially attributed to polymorphic CYP2D6 metabolism. The contribution of CYP3A, CYP2B6, fraction unbound, and other potential covariates remains unknown. This study aimed to investigate the contribution of in vivo activities of cytochrome P450 (CYP) 2D6 and 3A as well as other potential covariates (CYP2B6 genotype to the SNP g.15631G>T, fraction unbound, age, body weight, creatinine clearance) to the enantioselective pharmacokinetics of tramadol. Thirty patients with neuropathic pain and phenotyped as CYP2D6 extensive metabolizers were treated with a single oral dose of 100 mg tramadol. Multiple linear regressions were performed to determine the contribution of CYP activities and other potential covariates to the clearance of tramadol enantiomers. The apparent total clearances were 44.9 (19.1–102‐2) L/h and 55.2 (14.8–126.0) L/h for (+)‐ and (−)‐tramadol, respectively [data presented as median (minimum–maximum)]. Between 79 and 83% of the overall variation in apparent clearance of tramadol enantiomers was explained by fraction unbound, CYP2D6, and CYP3A in vivo activities and body weight. Fraction unbound explained 47 and 41% of the variation in clearance of (+)‐tramadol and (−)‐tramadol, respectively. Individually, CYP2D6 and CYP3A activities were shown to have moderate contribution on clearance of tramadol enantiomers (11–16% and 11–18%, respectively). In conclusion, factors affecting fraction unbound of drugs (such as hyperglycemia or co‐administration of drugs highly bound to plasma proteins) should be monitored, because this parameter dominates the elimination of tramadol enantiomers.