Genetically Polymorphic OCT1: Another Piece in the Puzzle of the Variable Pharmacokinetics and Pharmacodynamics of the Opioidergic Drug Tramadol

Abstract

We investigated whether tramadol or its active metabolite, O-desmethyltramadol, are substrates of the organic cation transporter OCT1 and whether polymorphisms in OCT1 affect tramadol and O-desmethyltramadol pharmacokinetics. Tramadol showed high permeability through parallel artificial membrane permeability assays (PAMPAs). Tramadol uptake in HEK293 cells did not change after OCT1 overexpression, and the concentrations of tramadol in the plasma of healthy volunteers were independent of their OCT1 genotypes. In contrast, O-desmethyltramadol showed low membrane permeability, and OCT1 overexpression increased O-desmethyltramadol uptake 2.4-fold. This increase in uptake was reversed by OCT1 inhibitors and absent when loss-of-function OCT1 variants were overexpressed. Volunteers carrying loss-of-function OCT1 polymorphisms had significantly higher plasma concentrations of O-desmethyltramadol (P = 0.002, n = 41) and significantly prolonged miosis, a surrogate marker of opioidergic effects (P = 0.005, n = 24). In conclusion, polymorphisms in OCT1 influence the pharmacokinetics of O-desmethyltramadol, presumably by affecting its uptake into liver cells, and thus may modulate the efficacy of tramadol treatment.

OCT1 Genetic Variants are Associated with Postoperative Morphine-Related Adverse Effects in Children

“…The heterozygotes have only one functional OCT1 allele and constitute about 40% of Caucasian population [19]. In case of loss of OCT1 function, there is reduced uptake of drugs in liver as also reported for tramadol and metformin [23,24]. Our findings (e.g., association between rs72552763 GAT deletion and high incidence of RD) are similar and to supportive of previously published associations between loss of function OCT1 and morphine and other drug effects.…”

“…Higher plasma morphine level will lead to greater incidences of morphine-induced PONV and RD. This SNP was reported to be associated with reduced metformin transport [26], lower tough concentration of metformin in diabetic patient [27], increased C max and reduced vomiting episodes following tropisetron and ondansetron administration [28], increased tramadol plasma level and increased miosis response in pain treatment [24]. We found that another SNP rs72552763 was also found to be associated with RD (p = 0.007).…”

“…We found that another SNP rs72552763 was also found to be associated with RD (p = 0.007). This SNP was reported to be related with lower trough values of metformin in diabetic patients [27], increased plasma concentration and higher clinical efficacy of tropisetron and ondansetron administered for nausea [28], increased probability of imatinib failure in chronic myeloid leukemia [29] and higher plasma level of tramadol [24]. Both of these SNPs rs12208357 and rs72552763 have been linked to decreased uptake in European-American population [26].…”

Analgesia and Opioids: A Pharmacogenetics Shortlist for Implementation in Clinical Practice

“…It is responsible for the uptake of positively charged compounds at physiological pH, such as morphine and the active metabolite of tramadol, O-desmethyltramadol (41 ). The role of SLC22A1 lossof-function polymorphisms (*2, *3, *4,*5, *6) on tramadol PK and PD was emphasized by the finding of increased O-desmethyltramadol plasma concentrations and prolonged contraction of the eye pupils (PD marker for opioid effect) in healthy volunteers (42 ). Another study in 205 adult postoperative patients on patientcontrolled analgesia found that those with 2 inactive SLC22A1 alleles had higher O-desmethyltramadol area under the concentration curve (AUC) and lower tramadol consumption during the first 24 h after surgery (43 ).…”

Discovery of Competitive and Noncompetitive Ligands of the Organic Cation Transporter 1 (OCT1; SLC22A1)

“…Genetic variants of OCT1 with reduced function have been associated with decreased response to metformin 4 as well as high systemic plasma levels of morphine and the active metabolite of the opioidergic drug tramadol. 5 Furthermore, administration of the calcium channel blocker verapamil (a potent inhibitor of OCT1) has been shown to reduce response to metformin, presumably through reducing hepatic drug levels. 6 In recognition of its critical role in drug disposition and response, OCT1 was included in a group of transporters of clinical importance by the International Transporter Consortium.…”