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No significant influence of OCT1 genotypes on the pharmacokinetics of morphine in adult surgical patients.

ABSTRACT: We investigated the impact of genetic variants in OCT1 (SLC22A1) on morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) pharmacokinetics in adult patients scheduled for major surgery. Blood samples were taken before and 5, 10, 15, 30, 45, 60 and 90 min after a bolus of morphine (0.15 mg/kg). Patients were genotyped for the genetic variants (rs12208357, rs34059508, rs72552763 and rs34130495) in OCT1. Eighty-six patients completed the trial. The mean difference (95% confidence interval) for dose adjusted morphine, M3G and M6G AUC was 0.9 (-0.7-2.4), -5.9 (-11.8 to -0.03) and -1.1 (-2.5-0.4) h/L*10^-6 , respectively, in patients with two reduced function alleles compared to patients with no reduced function alleles in OCT1. Accordingly, the (AUC_M3G/Dose )/(AUC_{morphine/Dose} ) and (AUC_M6G/Dose )/(AUC_{morphine/Dose} ) ratio was reduced, -1.8 (-3.2 to -0.4) and -0.4 (-0.7 to -0.03), respectively, when comparing the same groups. OCT1 variants had no influence on the experience of pain, adverse events or the number of PCA doses used. In conclusion, genetic variants in OCT1 had a small and clinically unimportant impact on the exposure of morphine after intravenous administration. Our results do not support pre-emptive genotyping for OCT1 prior to morphine administration in patients scheduled for major surgery.

SUBMITTER: Kuhlmann I

PROVIDER: S-EPMC9298338 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundSubanesthetic ketamine may reduce perioperative consumption of opioids. We studied whether intravenous S-ketamine alters the pharmacokinetics of oral morphine in healthy volunteers.MethodsIn this paired, randomized, double-blind, crossover trial, 12 participants under a 2-hour intravenous S-ketamine (0.57 mg/kg/h) or placebo infusion received oral morphine (0.2 mg/kg) at 30 minutes. Plasma concentrations of ketamine, morphine, and their major metabolites were quantified for 24 hours. The primary end point was area under the curve (AUC)0-24 of morphine. Other pharmacokinetic variables for morphine and its metabolites were studied as secondary end points. The data were analyzed as between-phase comparisons for each participant using Wilcoxon matched-pairs signed-rank tests (tmax) or paired t-tests on log-transformed variables (other variables).ResultsWhile the AUC0-24 was similar between the 2 phases, S-ketamine reduced the AUC0-1.5 of oral morphine by 69% (ratio to control, 0.31; 90% confidence interval [CI], 0.15-0.65; P = .0171) and increased its tmax from 0.5 (range, 0.50-1.5) to 1.0 hour (range, 0.50-4.0; P = .010). The AUC0-1.5 of morphine-6-glucuronide (M6G) was reduced by 84% (0.16; 90% CI, 0.07-0.37; P = .0025) and maximum plasma concentration (Cmax) by 43% (0.57; 90% CI, 0.40-0.81; P = .0155), while its tmax was increased from 1.5 (range, 1.0-2.0) to 4.0 (range, 1.0-8.0; P = .0094) hours by S-ketamine. Similarly, the AUC0-1.5 of morphine-3-glucuronide (M3G) was reduced by 85% (0.15; 90% CI, 0.05-0.43; P = .0083), and tmax increased from 1.0 (range, 0.5-1.5) to 4.0 hours (range, 1.0-8.0; P = .0063). In addition, the M6G-to-morphine and M3G-to-morphine metabolic AUC ratios were decreased by 47% (0.53; 90% CI, 0.39-0.71; P = .0033) and 52% (0.48; 90% CI, 0.27-0.85; P = .0043) during 0 to 1.5 hours and by 15% (0.85; 90% CI, 0.78-0.92; P = .0057) and 10% (0.90; 90% CI, 0.83-0.98; P = .0468) during 0 to 24 hours, respectively. One participant was excluded from the analyses due to vomiting in the S-ketamine phase.ConclusionsIntravenous S-ketamine inhibited the metabolism of oral morphine and delayed its absorption, resulting in a net reduction in the exposure to morphine during the first 1.5 hours. Intravenous S-ketamine may delay the absorption and impair the efficacy of orally administered analgesics and other drugs.

Project description:AimLarge interindividual variability in morphine pharmacokinetics (PK) could contribute to variability in morphine analgesia and adverse events. Respiratory depression (RD) and postoperative nausea and vomiting (PONV) are significant adverse drug response of intravenous morphine in the perioperative setting limiting its efficacy in achieving adequate surgical pain relief. OCT1 is a transporter in the liver that transports morphine from the bloodstream into hepatocytes. Earlier we reported association of genetic polymorphisms in OCT1 with morphine PK, and lower morphine clearance in Caucasian children as compared with African-American (AA) children. The aim of this study is to identify the association between common OCT1 genotypes affecting morphine's PK and clinically important postoperative morphine-related adverse outcomes.MethodsAfter obtaining institutional review board (IRB) approval and informed consents, 311 children ages 6-15 years, American Society of Anesthesiologists' physical status 1 or 2 scheduled for tonsillectomy who received standard anesthetic, surgical and postoperative care were recruited. Clinical data collected included postoperative pain scores, total opioid use, incidence of PONV and RD. Four nonsynonymous SNPs of the OCT1 gene (rs12208357, rs34130495, rs72552763 and rs34059508) in each patient were genotyped using commercially available TaqMan assays. We investigated the genetic association of OCT1 with incidences of postoperative RD and PONV.ResultsCaucasian and AA children differed significantly in the incidence of obstructive sleep apnea (p < 0.001) and total morphine use (p = 0.028). There were incidences of prolonged post anesthesia care unit stay in 7% of Caucasian children, while no such incidences were observed for AA children (p = 0.05). OCT1 polymorphism rs12208357 was associated with high incidences of PONV and PONV leading to prolonged post anesthesia care unit stay (p < 0.05). A significant association was also found between rs72552763 GAT deletion and high incidence of RD (p = 0.007).ConclusionChildren with certain OCT1 genotypes are associated with higher risk for RD and PONV following morphine administration leading to prolonged hospital stay. The OCT1 transporters' effects on morphine's PK could explain this association.

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No significant influence of OCT1 genotypes on the pharmacokinetics of morphine in adult surgical patients.

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