morphine-3-glucuronide and Kidney-Failure--Chronic

We studied the influence of three factors on drug disposition: genetic polymorphism, impaired renal excretion of drug metabolites, and the possible elimination by hemodialysis (HD), using codeine as a model drug.. Based on the genotyping of three CYP2D6 polymorphisms in 228 HD patients, nine extensive metabolizers (EMs) and two poor metabolizers (PMs) were given a single oral dose of 50 mg codeine phosphate. Plasma concentrations of its metabolites codeine-6-glucuronide (C6G), morphine-3-glucuronide (M3G), and morphine-6-glucuronide (M6G) were determined after 2, 4, 6, 8 and 24 h (beginning of the HD session) and again after 4 h of HD (28 h). Codeine metabolites in plasma were quantitated by liquid chromatography-mass spectrometry (LC-MS).. The concentrations of C6G in plasma were high and similar in EMs and PMs. Two hours after the codeine intake, the mean concentration of M3G was 210 nM in EMs vs. 3.5 nM in PMs. The M6G metabolite concentrations could be quantitated in EMs but were below the limit of quantification in PMs (<1 nM). All three codeine metabolites/glucuronides remained unchanged or even increased until the start of HD, and thereafter, the concentrations decreased dramatically during the HD procedure.. Formation of the codeine metabolites M3G and M6G was dependent on the CYP2D6 genotype, as previously shown in healthy individuals. Elimination of glucuronides in these patients was absent until HD was performed. These factors need to be taken into consideration when drugs metabolized by CYPs are prescribed in HD patients.

Topics: Administration, Oral; Aged; Biotransformation; Chromatography, Liquid; Codeine; Cytochrome P-450 CYP2D6; Female; Gene Frequency; Genotype; Humans; Kidney Failure, Chronic; Male; Middle Aged; Morphine Derivatives; Phenotype; Polymorphism, Genetic; Renal Dialysis; Spectrometry, Mass, Electrospray Ionization

The pharmacokinetics of morphine and its glucuronide metabolites were investigated in three groups of patients with kidney failure (nondialyzed, receiving dialysis, and transplantation) and compared with a group of normal healthy volunteers. Patients in all three renal groups were undergoing surgical procedures (nondialyzed group undergoing arteriovenous fistula formation, dialysis group undergoing placement of a peritoneal dialysis catheter, and the transplant group undergoing live donor kidney transplant). A sensitive, specific high-performance liquid chromatographic assay was used to quantitate morphine, morphine-3-glucuronide, and morphine-6-glucuronide. Patients with kidney failure had a significantly increased morphine area under the curve (AUC) compared with control subjects. There was also an increase in the metabolites morphine-3-glucuronide and morphine-6-glucuronide that was severalfold greater than the increase in morphine AUC. This metabolite accumulation was reversed by kidney transplantation, providing an elegant confirmation on the role of the kidney in morphine pharmacology.

Topics: Adult; Humans; Kidney Failure, Chronic; Kidney Transplantation; Metabolic Clearance Rate; Middle Aged; Morphine; Morphine Derivatives; Peritoneal Dialysis

The influence of renal failure on the disposition of morphine and its metabolites was studied in nine patients with end-stage renal failure undergoing transplantation, and compared with five healthy anaesthetized patients. All patients received morphine sulphate pentahydrate 10 mg i.v. over 30 s, as part of a balanced anaesthetic technique. Venous blood samples were collected for up to 24 h, and plasma concentrations of morphine, morphine-3-glucuronide (M3G), and morphine-6-glucuronide (M6G) assayed by a differential radioimmunoassay method. There were no differences between the two groups for morphine elimination half-life (renal failure: 290 min; anaesthetized controls: 286 min), or clearance (renal failure: 533 ml min-1; controls 741 ml min-1). However, the volume of distribution at steady state was greater in the control group (241 litre v. 141 litre; P = 0.002). The peak concentrations of M3G and M6G were greater in the renal transplant patients (P = 0.001 and P = 0.01, respectively), as were the AUC (0-24 h) (P = 0.002 and P = 0.002). M6G has been shown to possess analgesic properties in both man and experimental animals, and therefore the increased AUC for M6G may contribute to the prolonged effect seen with morphine when given to patients with impaired renal function.

Topics: Adult; Anesthesia, General; Half-Life; Humans; Kidney Failure, Chronic; Kidney Transplantation; Metabolic Clearance Rate; Middle Aged; Morphine; Morphine Derivatives

The kinetics of morphine and its glucuronidated metabolites were investigated in seven patients with advanced renal failure. The terminal elimination half life of morphine varied between 1.5 and 4.0 h (mean 2.4 h), the volume of distribution between 2.5 and 6.3 l X kg-1 (mean 4.4 l X kg-1) and the total plasma clearance between 13.3 and 31.3 l X min-1 X kg-1 (mean 21.1 l X kg-1). There were no statistically significant differences between the pharmacokinetic data in the uraemic patients and in a control group of cancer patients with normal kidney function. The concentrations of the glucuronidated metabolites rapidly rose to levels above those of morphine. The elimination half-life of M3G varied between 14.5 and 118.8 h (mean 49.6 h) in the renal failure patients, which is distinctly different from the 2.4 to 6.7 h (mean 4.0 h) found in patients with normal kidney function. There was a significant correlation between the half-life of M3G and renal function estimated as serum urea. Thus, the metabolism of morphine in patients with kidney disease is not significantly impaired. The clinical importance of the high concentrations of glucuronides in uraemic patients is not known.

Topics: Adult; Aged; Enterohepatic Circulation; Female; Half-Life; Humans; Kidney Failure, Chronic; Kinetics; Male; Middle Aged; Morphine; Morphine Derivatives; Uremia

Topics: Humans; Kidney Failure, Chronic; Kinetics; Morphine; Morphine Derivatives