ABCC3 genetic variants are associated with postoperative morphine-induced respiratory depression and morphine pharmacokinetics in children

Chidambaran, Vidya; Venkatasubramanian, Raja; Zhang, X; Martin, Lisa J.; Niu, Jing; Mizuno, Tomoyuki; Fukuda, Tsuyoshi; Meller, Jarosław; Vinks, Alexander A.; Sadhasivam, Senthilkumar

doi:10.1038/tpj.2015.98

Cited by 27 publications

(11 citation statements)

References 44 publications

(41 reference statements)

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“…The importance of the ABCB1 polymorphism was also confirmed by investigating the risk of respiratory depression in response to morphine administration (Sadhasivam et al., ). A similar role in influencing the risk of morphine induced respiratory depression has been recently established for the gene ABCC3 (coding for a transporter that facilitates hepatic morphine metabolite efflux) (Venkatasubramanian et al., ; Sadhasivam et al., ; Chidambaran et al., ). OCT1, a member of the organic cation transporters (OCTs) family, mediates cellular uptake of morphine into hepatocytes.…”

Section: Assessmentmentioning

confidence: 68%

Update of the Scientific Opinion on opium alkaloids in poppy seeds

Knutsen¹,

Alexander²,

Barregård³

et al. 2018

EFS2

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Poppy seeds are obtained from the opium poppy (Papaver somniferum L.). They are used as food and to produce edible oil. The opium poppy plant contains narcotic alkaloids such as morphine and codeine. Poppy seeds do not contain the opium alkaloids, but can become contaminated with alkaloids as a result of pest damage and during harvesting. The European Commission asked EFSA to provide an update of the Scientific Opinion on opium alkaloids in poppy seeds. The assessment is based on data on morphine, codeine, thebaine, oripavine, noscapine and papaverine in poppy seed samples. The CONTAM Panel confirms the acute reference dose (ARfD) of 10 lg morphine/kg body weight (bw) and concluded that the concentration of codeine in the poppy seed samples should be taken into account by converting codeine to morphine equivalents, using a factor of 0.2. The ARfD is therefore a group ARfD for morphine and codeine, expressed in morphine equivalents. Mean and high levels of dietary exposure to morphine equivalents from poppy seeds considered to have high levels of opium alkaloids (i.e. poppy seeds from varieties primarily grown for pharmaceutical use) exceed the ARfD in most age groups. For poppy seeds considered to have relatively low concentrations of opium alkaloids (i.e. primarily varieties for food use), some exceedance of the ARfD is also seen at high levels of dietary exposure in most surveys. For noscapine and papaverine, the available data do not allow making a hazard characterisation. However, comparison of the dietary exposure to the recommended therapeutical doses does not suggest a health concern for these alkaloids. For thebaine and oripavine, no risk characterisation was done due to insufficient data. However, for thebaine, limited evidence indicates a higher acute lethality than for morphine and the estimated exposure could present a health risk.

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Section: Assessmentmentioning

confidence: 68%

Update of the Scientific Opinion on opium alkaloids in poppy seeds

Knutsen¹,

Alexander²,

Barregård³

et al. 2018

EFS2

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“…The disposition of morphine-6-G is of particular interest since it is an active metabolite. The appearance of morphine glucuronides in the systemic circulation appears to be associated with a promoter region variant of ABCC3 (c.-211C>T, rs4793665) in pediatric patients, with the CC genotypes having a higher glucuronide level than the CT and TT genotypes ( Venkatasubramanian et al, 2014 ; Chidambaran et al, 2017 ). Even though morphine is not known to be a substrate of MRP3, a link between apparent decreased morphine clearance and the c.-211C>T variant has been found in pediatric patients ( Hahn et al, 2020 ).…”

Section: Effects Of Pharmacogenetics On Conjugate Dispositionmentioning

confidence: 99%

“…This is suggested to be due to a shift from the urinary excretion pathway to biliary excretion: Patients with the CT or TT genotypes had lower MRP3 activity than those with the CC genotype, leading to increased excretion of the glucuronides to the bile by MRP2, and a subsequent increase in enterohepatic recycling and morphine exposure. Furthermore, some ABCC3 intronic variants were found to be associated with a longer postoperative unit care stay, due to respiratory depression as a side effect of morphine treatment ( Chidambaran et al, 2017 ).…”

Section: Effects Of Pharmacogenetics On Conjugate Dispositionmentioning

confidence: 99%

The Role of Uptake and Efflux Transporters in the Disposition of Glucuronide and Sulfate Conjugates

et al. 2022

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Glucuronidation and sulfation are the most typical phase II metabolic reactions of drugs. The resulting glucuronide and sulfate conjugates are generally considered inactive and safe. They may, however, be the most prominent drug-related material in the circulation and excreta of humans. The glucuronide and sulfate metabolites of drugs typically have limited cell membrane permeability and subsequently, their distribution and excretion from the human body requires transport proteins. Uptake transporters, such as organic anion transporters (OATs and OATPs), mediate the uptake of conjugates into the liver and kidney, while efflux transporters, such as multidrug resistance proteins (MRPs) and breast cancer resistance protein (BCRP), mediate expulsion of conjugates into bile, urine and the intestinal lumen. Understanding the active transport of conjugated drug metabolites is important for predicting the fate of a drug in the body and its safety and efficacy. The aim of this review is to compile the understanding of transporter-mediated disposition of phase II conjugates. We review the literature on hepatic, intestinal and renal uptake transporters participating in the transport of glucuronide and sulfate metabolites of drugs, other xenobiotics and endobiotics. In addition, we provide an update on the involvement of efflux transporters in the disposition of glucuronide and sulfate metabolites. Finally, we discuss the interplay between uptake and efflux transport in the intestine, liver and kidneys as well as the role of transporters in glucuronide and sulfate conjugate toxicity, drug interactions, pharmacogenetics and species differences.

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“…Morphine dosing was consistent with previous studies examining pediatric tonsillectomy pain management. 15,16 Patients were maintained with isoflurane titrated to a range from 0.8 to 1 MAC (minimum alveolar concentration) with a mixture of air and oxygen to maintain an FiO 2 (fraction of inspired oxygen) of less than 30% for the duration of the procedure and until the completion of the surgical procedure when the patient was ready for transport to the PACU. All patients received antiemetic therapy consisting of ondansetron (0.15 mg/kg) and dexamethasone (0.25 mg/kg).…”

Section: Methodsmentioning

confidence: 99%

Double-Blind Randomized Placebo-Controlled Trial of Single-Dose Intravenous Acetaminophen for Pain Associated With Adenotonsillectomy in Pediatric Patients With Sleep-Disordered Breathing

Thung

Elmaraghy

Barry

et al. 2017

The Journal of Pediatric Pharmacology and Therapeutics

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OBJECTIVES Adequate pain control is an important component in the postoperative outcome for pediatric adenotonsillectomy patients with sleep-disordered breathing (SDB). Intravenous acetaminophen appears to be a favorable analgesic adjunct owing to its predictable pharmacokinetics and opioid-sparing effects; however, its role in pediatric adenotonsillectomy pain management remains unclear. METHODSIn this prospective, randomized, double-blinded, controlled study, subjects with the diagnosis of SDB, aged 2 to 8 years, who required extended postoperative admission, received intravenous acetaminophen (15 mg/kg) or saline placebo intraoperatively in addition to morphine (0.1 mg/kg) for postoperative surgical analgesia. Pain scores in the postanesthesia care unit (PACU) using the FLACC (Faces, Leg, Activity, Cry, Consolability) score were used to determine the need for supplemental analgesic agents in the PACU. The PACU time and time to the first request for pain medication on the inpatient ward were also measured.

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ABCC3 genetic variants are associated with postoperative morphine-induced respiratory depression and morphine pharmacokinetics in children

Cited by 27 publications

References 44 publications

Update of the Scientific Opinion on opium alkaloids in poppy seeds

Update of the Scientific Opinion on opium alkaloids in poppy seeds

The Role of Uptake and Efflux Transporters in the Disposition of Glucuronide and Sulfate Conjugates

Double-Blind Randomized Placebo-Controlled Trial of Single-Dose Intravenous Acetaminophen for Pain Associated With Adenotonsillectomy in Pediatric Patients With Sleep-Disordered Breathing

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