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OCT1 genetic variants influence the pharmacokinetics of morphine in children.

ABSTRACT: Large interindividual variability in morphine disposition could contribute to unpredictable variability in morphine analgesia and adverse events. Caucasian children have more adverse effects and slower morphine clearance than African-American children. To study variations in intravenous morphine pharmacokinetics in children, we examined the influence of genetic polymorphisms in OCT1.In 146 children undergoing adenotonsillectomy, 146 concentration-time profiles (2-4 measurements per patient) were available. Population pharmacokinetic analysis characterized the profiles in NONMEM(®) and tested OCT1 variants as covariates.Allometrically scaled post hoc Bayesian morphine clearance in homozygotes of loss-of-function OCT1 variants (n = 9, OCT1*2-*5/*2-*5) was significantly lower (20%) than in wild-type (n = 85, OCT1*1/*1) and heterozygotes (n = 52, OCT1*1/*2-*5; p < 0.05).Besides bodyweight, OCT1 genotypes play a significant role in intravenous morphine pharmacokinetics. Relatively high allelic frequencies of defective OCT1 variants among Caucasians may explain their lower morphine clearance and possibly higher frequencies of adverse events compared with African-American children. Original submitted 21 December 2012; Revision submitted 7 May 2013.

SUBMITTER: Fukuda T

PROVIDER: S-EPMC4116670 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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OCT1 genetic variants influence the pharmacokinetics of morphine in children.

Fukuda Tsuyoshi T Chidambaran Vidya V Mizuno Tomoyuki T Venkatasubramanian Raja R Ngamprasertwong Pornswan P Olbrecht Vanessa V Esslinger Hope R HR Vinks Alexander A AA Sadhasivam Senthilkumar S

Pharmacogenomics 20130701 10

<h4>Aim</h4>Large interindividual variability in morphine disposition could contribute to unpredictable variability in morphine analgesia and adverse events. Caucasian children have more adverse effects and slower morphine clearance than African-American children. To study variations in intravenous morphine pharmacokinetics in children, we examined the influence of genetic polymorphisms in OCT1.<h4>Methods</h4>In 146 children undergoing adenotonsillectomy, 146 concentration-time profiles (2-4 me ...[more]

PMID: 23859569

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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.

Project description:BackgroundObesity increases susceptibility to chronic pain, increases metabolism, and is associated with obstructive sleep apnea syndrome (OSAS), all which can complicate perioperative pain management of patients. In addition, obesity and OSAS can cause elevation of the adipose-derived hormone leptin, which increases metabolism. We hypothesized that obesity along with sleep apnea and leptin independently enhance morphine pharmacokinetics.MethodsChildren 5-12 years of age who were presenting for surgery were administered a morphine dose of 0.05 mg/kg. Blood was collected at baseline and at subsequent preset times for pharmacokinetic analysis of morphine and its metabolites. Three groups were studied: a nonobese group with severe OSAS, an obese group with severe OSAS, and a control group.ResultsThirty-four patients consisting of controls (n = 16), nonobese/OSAS (n = 8), and obese/OSAS (n = 10) underwent analysis. The obese/OSAS group had a higher dose-adjusted mean maximum morphine concentration (CMAX) over 540 minutes compared to the controls (P < .001) and those with only OSAS (P = .014). The obese/OSAS group also had lower volume of distribution (Vd) when compared to OSAS-only patients (P = .007). In addition, those in the obese/OSAS group had a higher morphine 3-glucuronide (M3G) maximum concentration (P = .012) and a higher ratio of M3G to morphine than did the control group (P = .011). Time to maximum morphine 6-glucuronide (M6G) concentration was significantly lower in both nonobese/OSAS and obese/OSAS groups than in the control group (P < .005). C-reactive protein (CRP), interleukin (IL)-10, and leptin were all higher in the obese/OSAS group than in controls (P = .004, 0.026, and <0.001, respectively), and compared to OSAS-only patients, CRP (P = .013) and leptin (P = .002) levels were higher in the obese/OSAS group.ConclusionsThe combination of obesity and OSAS was associated with an increase in morphine metabolism compared with that in normal-weight controls. Our previous study in mice demonstrated that obesity from leptin deficiency decreased morphine metabolism, but that metabolism normalized after leptin replacement. Leptin may be a cause of the increased morphine metabolism observed in obese patients.

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.

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OCT1 genetic variants influence the pharmacokinetics of morphine in children.

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OCT1 genetic variants influence the pharmacokinetics of morphine in children.

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