Effects of type 1 and type 2 diabetes on the pharmacokinetics of tramadol enantiomers in patients with neuropathic pain phenotyped as cytochrome P450 2D6 extensive metabolizers

• Published in: Journal of pharmacy and pharmacology 2014-09, Vol.66 (9), p.1222-1230
• Main Authors: de Moraes, Natália Valadares, Lauretti, Gabriela Rocha, Lanchote, Vera Lucia
• Format: Article
• Language: English
• Subjects: Adult; Analgesics, Opioid - metabolism; Analgesics, Opioid - pharmacokinetics; Analgesics, Opioid - therapeutic use; Area Under Curve; Blood Glucose - metabolism; Cytochrome P-450 CYP2D6 - metabolism; diabetes; Diabetes Mellitus, Type 1 - blood; Diabetes Mellitus, Type 1 - complications; Diabetes Mellitus, Type 1 - metabolism; Diabetes Mellitus, Type 2 - blood; Diabetes Mellitus, Type 2 - complications; Diabetes Mellitus, Type 2 - metabolism; Diabetic Neuropathies - drug therapy; Female; fraction unbound; Humans; Male; Middle Aged; Neuralgia - drug therapy; O-desmethyltramadol; pharmacokinetics; Phenotype; Stereoisomerism; tramadol; Tramadol - metabolism; Tramadol - pharmacokinetics; Tramadol - therapeutic use
• ISSN: 0022-3573; 2042-7158
• DOI: 10.1111/jphp.12255

Objectives The aim of this study was to evaluate the influence of poorly controlled type 1 (T1DM) and type 2 diabetes mellitus (T2DM) on the pharmacokinetics and metabolism of tramadol enantiomers in patients with neuropathic pain. Methods Nondiabetic patients (control group, n = 12), patients with T1DM (n = 9) or T2DM (n = 9), all with neuropathic pain and phenotyped as cytochrome P450 2D6 extensive metabolizers, received a single oral dose of 100 mg racemic tramadol. Serial blood samples were collected over a 24‐h period. Key findings Patients with T1DM showed reduced Cmax of both tramadol enantiomers. The plasma concentrations of the active (+)‐M1 were significantly reduced in T1DM (area under the curve plasma concentration versus time (AUC∞): 313.1 ng·h/ml) when compared with nondiabetic patients (AUC∞: 1246.6 ng·h/ml). The fraction unbound of (+)‐M1 was increased in patients with T1DM. Patients with T1DM and T2DM showed reduced AUC and increased fraction unbound of (−)‐M1. Conclusions The reduced total plasma concentrations of the active (+)‐M1 in patients with T1DM may not be of clinical relevance because they are counterbalanced by the increased fraction unbound.