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.
OBJECTIVE
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.


RESULTS
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.
Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil.
Natália Valadares
NV
de Moraes
Gabriela Rocha
GR
Lauretti
Vera Lucia
VL
Lanchote
D000328:Adult; D000701:Analgesics, Opioid / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D001786:Blood Glucose / Q000378:metabolism; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism*; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000150:complications / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000150:complications / Q000378:metabolism*; D003929:Diabetic Neuropathies / Q000188:drug therapy*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009437:Neuralgia / Q000188:drug therapy*; D010641:Phenotype; D013237:Stereoisomerism; D014147:Tramadol / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use
D000701:Analgesics, Opioid; D001786:Blood Glucose; D014147:Tramadol; D019389:Cytochrome P-450 CYP2D6
O-desmethyltramadol; diabetes; fraction unbound; pharmacokinetics; tramadol