Metabolism of the analgesic drug ULTRAM ® (tramadol hydrochloride) in humans: API-MS and MS/MS characterization of metabolites

Abstract

1. Metabolism of the analgesic agent tramadol hydrochloride has been investigated after a single oral administration of tramadol to three male volunteers (100 mg/subject), and a urine pool (4-12h) was obtained. 2. Unchanged tramadol and a total of 23 metabolites, consisting of 11 Phase I metabolites (M1-11) and 12 conjugates (seven glucuronides, five sulphates), were profiled, characterized and tentatively identified in urine on the basis of API ionspray-MS and MS/MS data. 3. Of the metabolites, five (M1-5) had been previously identified. 4. The metabolites were formed via the following six metabolic pathways: (1) O-demethylation, (2) N-demethylation, (3) cyclohexyl oxidation, (4) oxidative N-dealkylation, (5) dehydration and (6) conjugation. 5. Pathways 1-3 appear to be major routes, forming seven O-desmethyl/N-desmethyl and hydroxycyclohexyl metabolites. 6. Pathways 1-3 in conjunction with pathway 6 produced seven glucuronides along with five sulphates. 7. In addition, the in vitro metabolism of tramadol was conducted using a human liver microsomal fraction in the presence of an NADPH-generating system. Unchanged tramadol (82% of the sample) plus eight metabolites (M1, M2, M4-6, tramadol-N-oxide (M31), OH-cyclohexyl-M1 (M32) and dehydrated tramadol-N-oxide), were profiled and tentatively identified on the basis of MS and MS/MS data.

Physiologically Based Pharmacokinetic Predictions of Tramadol Exposure Throughout Pediatric Life: an Analysis of the Different Clearance Contributors with Emphasis on CYP2D6 Maturation

“…As has been described above, the clearance prediction for this PBPK model is based on three hepatic components (CYP2D6, CYP3A4, and CYP2B6) and one renal component (GFR). Possible explanations for an underprediction are (i) incorrect maturation function for either of the implemented CYP enzymes, (ii) other metabolic pathways contributing to tramadol's metabolism in pediatric life (FMO, CYP3A7) (12,38), or (iii) neglecting other minor pathways in tramadol metabolism (10). Therefore, the total clearance of tramadol was decomposed in its constituents and compared to in vivo observations, when possible.…”

“…Additionally, tramadol is inactivated to N-desmethyltramadol (NDT) by CYP3A4 and CYP2B6. Secondary metabolism involves further oxidation and phase 2 conjugative reactions (10). In early life, however, these primary metabolic pathways mature differently, and as a consequence, not only the absolute value of the clearance but also relative contributions of the different eliminating pathways may change over time.…”

Tramadol efficacy in patients with postoperative pain in relation to CYP2D6 and MDR1 polymorphisms

“…There are three major metabolic pathways via three distinct cytochrome P450 enzymes CYP2D6, CYP3A, and CY-P2B6 forming O-and N-demethylated metabolites. Major active metabolite O-demethyltramadol is, however, formed in the liver predominantly via CYP2D6 enzyme (1,2). Pharmacokinetics of tramadol and its metabolites is indeed stereoselective and displays high interindividual variability correlating with polymorphic activity of CYP2D6 in the population (3)(4)(5)(6)(7).…”

Unexceptional Seizure Potential of Tramadol or Its Enantiomers or Metabolites in Mice

“…Tramadol produces its multimodal antinociceptive and analgesic effects via two mechanisms (Raffa and Friderichs, 1996): one is opioid, and the other is nonopioid (Hennies et al, 1988;Friderichs et al, 1991Friderichs et al, , 1992Raffa et al, 1992Raffa et al, , 1993Raffa et al, , 1995Dayer et al, 1997;Ide et al, 2006). The opioid component involves weak affinity (approximately 1 M) of the parent drug and approximately 300-fold greater affinity of the M1 metabolite of tramadol (Wu et al, 2002) for -opioid receptors (Hennies et al, 1988;Raffa et al, 1992;Lai et al, 1996;Gillen et al, 2000). The nonopioid component is related to inhibition of neuronal 5-hydroxytryptamine (5-HT; serotonin) and norepinephrine reuptake (Friderichs et al, 1991;Codd et al, 1995).…”