Route‐dependent stereoselective pharmacokinetics of tramadol and its active O‐demethylated metabolite in rats

Abstract

The effects of route of administration on the stereoselective pharmacokinetics of tramadol (T) and its active metabolite (M1) were studied in rats. A single 20 mg/kg dose of racemic T was administered through intravenous, intraperitoneal, or oral route to different groups of rats, and blood and urine samples were collected. Samples were analyzed using chiral chromatography, and pharmacokinetic parameters (mean +/- SD) were estimated by noncompartmental methods. Following intravenous injection, there was no stereoselectivity in the pharmacokinetics of T. Both enantiomers showed clearance values (62.5 +/- 27.2 and 64.4 +/- 39.0 ml/min/kg for (+)- and (-)-T, respectively) that were equal or higher than the reported liver blood flow in rats. Similar to T, the area under the plasma concentration-time curves (AUCs) of M1 did not exhibit stereoselectivity after intravenous administration of the parent drug. However, the systemic availability of (+)-T was significantly (P < 0.05) higher than that of its antipode following intraperitoneal (0.527 +/- 0.240 vs. 0.373 +/- 0.189) and oral (0.307 +/- 0.136 vs. 0.159 +/- 0.115) administrations. The AUC of the M1 enantiomers, on the other hand, remained mostly nonstereoselective regardless of the route of administration. Pharmacokinetic analysis indicated that the stereoselectivity in the pharmacokinetics of oral T is due to stereoselective first pass metabolism in the liver and, possibly, in the gastrointestinal tract. The direction and extent of stereoselectivity in the pharmacokinetics of T and M1 in rats were in agreement with those previously reported in humans, suggesting that the rat may be a suitable model for enantioselective studies of T pharmacokinetics.

The postoperative analgesic efficacy of intraperitoneal tramadol compared to normal saline or intravenous tramadol in laparoscopic cholecystectomy

“…tramadol when used during CO 2 insufflation; this can probably be explained by the fact that tramadol is decomposed in acidic and basic environments [17]. Another explanation has been suggested by Parasprampuria and colleagues [18]. They have shown that in rats the route of administration of tramadol affected the stereoselective pharmacokinetics of this drug; after i.v.…”

“…administration of tramadol, the blood concentration of the enantiomers, although lower than that after the i.v. injection, was substantial and stereoselective in favour of the (1)-enantiomer [18]. The manufactured tramadol is a racemic mixture of two complementary and synergistic enantiomers [15].…”

Advances in Exotic Mammal Clinical Therapeutics

“…The conversion to the M1 metabolite is variable among species, but it is known that it is produced in rats, mice, and rabbits. [78][79][80] In the United States, only the oral formulation is available. In humans, less respiratory depression and constipation are seen with tramadol than with other m-agonist opioids.…”

Anesthesia, Analgesia, and Sedation of Small Mammals

“…It is active at opiate, alpha-adrenergic, and serotonergic receptors. 90,112,123 In the United States, only the PO formulation is available. The conversion to the M1 metabolite is variable among species, but it is known that it is produced in rats, mice, and rabbits.…”

“…109 Tramadol is a very weak μ agonist, but the O-desmethyl metabolite (M1) is a much more potent agonist. 57 The pharmacokinetics of tramadol have been evaluated in rats 34,90,127 and rabbits, 112 but analgesic plasma concentrations have not yet been established. 90,112,123 In the United States, only the PO formulation is available.…”