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

Objectives The aim of this study was to evaluate the influence of poorly controlled type 1 ( T1 DM) and type 2 diabetes mellitus ( T2 DM) on the pharmacokinetics and metabolism of tramadol enantiomers in patients with neuropathic pain. Methods Nondiabetic patients (control group, n = 12), patients with T1 DM ( n = 9) or T2 DM ( n = 9), all with neuropathic pain and phenotyped as cytochrome P450 2 D6 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 T1 DM showed reduced Cmax of both tramadol enantiomers. The plasma concentrations of the active (+)- M1 were significantly reduced in T1 DM (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 T1 DM. Patients with T1 DM and T2 DM showed reduced AUC and increased fraction unbound of (−)- M1. Conclusions The reduced total plasma concentrations of the active (+)- M1 in patients with T1 DM may not be of clinical relevance because they are counterbalanced by the increased fraction unbound. [ABSTRACT FROM AUTHOR]