Study of the pharmacokinetic changes of Tramadol in diabetic rats

Abstract

BackgroundBesides the pathological states, diabetes mellitus may also alter the hepatic biotransformation of pharmaceutical agents. It is advantageous to understand the effect of diabetes on the pharmacokinetic of drugs. The objective of this study was to define the pharmacokinetic changes of tramadol and its main metabolites after in vivo intraperitoneal administration and ex vivo perfused liver study in diabetic rat model.Tramadol (10 mg/kg) was administered to rats (diabetic and control groups of six) intraperitoneally and blood samples were collected at different time points up to 300 min. In a parallel study, isolated liver perfusion was done (in diabetic and control rats) by Krebs-Henseleit buffer (containing 500 ng/ml tramadol). Perfusate samples were collected at 10 min intervals up to 180 min. Concentration of tramadol and its metabolites were determined by HPLC.ResultsTramadol reached higher concentrations after i.p. injection in diabetics (Cmax of 1607.5 ± 335.9 ng/ml) compared with control group (Cmax of 561.6 ± 111.4). M1 plasma concentrations were also higher in diabetic rats compared with control group. M2 showed also higher concentrations in diabetic rats. Comparing the concentration levels of M1 in diabetic and control perfused livers, showed that in contrast to intact animals, the metabolic ratios of M1 and M5 (M/T) were significantly higher in diabetic perfused liver compared to those of control group.ConclusionsThe pharmacokinetic of tramadol and its three metabolites are influenced by diabetes. As far as M1 is produced by Cyp2D6, its higher concentration in diabetic rats could be a result of induction in Cyp2D6 activity, while higher concentrations of tramadol can be explained by lower volume of distribution.

Tramadol hydrochloride: Pharmacokinetics, pharmacodynamics, adverse side effects, co-administration of drugs and new drug delivery systems

“…This drug is structurally related to 26 codeine and morphine, but it is 6000-times less potent than 27 morphine and 10-times less potent than codeine [1][2][3]. It appeared 28 in the 1970s, but only approved by the Food and Drug Administra-29 tion (FDA) in 1995 for the management, treatment and relief of 30 moderate to severe pain conditions [4][5][6].…”

“…About 20% of the drug is bound to plasma proteins and the 48 mean half-life is ca. 6 h [1,4,6]. TrHC is extensively metabolized in 49 the liver via cytochrome isoenzymes P450 2D6, and P450 2B6 and 50 P450 3A4, to O-desmethyltramadol (M1) and N-desmethyltrama-51 dol (M2) respectively, being the main phase-1 metabolites.…”

“…These 52 are further metabolized to three secondary metabolites, namely 53 N,N-didesmethyltramadol, N,N,O-tridesmethyltramadol and N,O-54 desmethyltramadol. All metabolites are finally conjugated with 55 glucuronic acid and sulfate before excretion in urine [1,5,10]. 56…”

“…The remaining drug is eliminated in the feces, therefore biliary 60 excretion is negligible [1,4,5]. 61…”

Commentary on: “study of the pharmacokinetic changes of tramadol in diabetic rats” is the handicapped renal pathway in DMIS contributing for the increased bioavailability of tramadol?

“…I read with interest a recently published article in your esteemed journal by Lavasani et al, entitled “Study of the pharmacokinetic changes of Tramadol in diabetic rats” [1]. Lavasani et al, have evaluated the influence of full-blown diabetes on the pharmacokinetic disposition of tramadol using a rat model of diabetes mellitus induced by streptozotocin (DMIS) [1].…”