Association of UGT2B7 and ABCB1 genotypes with morphine-induced adverse drug reactions in Japanese patients with cancer

Fujita, Ken‐ichi; Ando, Yumiko; Yamamoto, Wataru; Miya, Toshimichi; Endo, Hisashi; Sunakawa, Yu; Araki, Kazuhiro; Kodama, Keiji; Nagashima, Fumio; Ichikawa, Wataru; Narabayashi, Masaru; Akiyama, Yoshitsugu; Kawara, Kaori; Shiomi, Mari; Ogata, Hiroyasu; Iwasa, Hiroyasu; Okazaki, Yasushi; Hirose, Takashi; Sasaki, Yasutsuna

doi:10.1007/s00280-009-1029-2

Cited by 86 publications

(68 citation statements)

References 31 publications

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“…A higher frequency of opioid-related adverse events such as sweating and sedation was reported in 3435TT genotyped individuals receiving remifentanil for spinal fusion surgery (33 ). Other SNPs in ABCB1, 1236CϾT (rs1128503) and 2677GϾT/A (rs2032582), have also been found to be related to adverse events (26,32,34,35 ). Other studies, including one in a pediatric population, could not confirm this increased risk for adverse events in carriers of the 3435T allele [see online Supplemental Table 3; ABCB1, references…”

Section: Abcb1mentioning

confidence: 96%

“…Adult Japanese patients (n ϭ 32) carrying the UGT2B7*2 allele reported less nausea while on oral morphine therapy for cancer pain than did patients carrying the wild-type UGT2B7 allele (26 ). However, not all clinical studies found an effect of these UGT2B7 polymorphisms on morphine PK or PD [see online Supplemental Table 3; UGT2B7, references (1-4 )].…”

Section: Ugt2b7mentioning

confidence: 99%

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Analgesia and Opioids: A Pharmacogenetics Shortlist for Implementation in Clinical Practice

et al. 2017

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BACKGROUND The use of opioids to alleviate pain is complicated by the risk of severe adverse events and the large variability in dose requirements. Pharmacogenetics (PGx) could possibly be used to tailor pain medication based on an individual's genetic background. Many potential genetic markers have been described, and the importance of genetic predisposition in opioid efficacy and toxicity has been demonstrated in knockout mouse models and human twin studies. Such predictors are especially of value for neonates and young children, in whom the assessment of efficacy or side effects is complicated by the inability of the patient to communicate this properly. The current problem is determining which of the many potential candidates to focus on for clinical implementation. CONTENT We systematically searched publications on PGx for opioids in 5 databases, aiming to identify PGx markers with sufficient robust data and high enough occurrence for potential clinical application. The initial search yielded 4257 unique citations, eventually resulting in 852 relevant articles covering 24 genes. From these genes, we evaluated the evidence and selected the most promising 10 markers: cytochrome P450 family 2 subfamily D member 6 (CYP2D6), cytochrome P450 family 3 subfamily A member 4 (CYP3A4), cytochrome P450 family 3 subfamily A member 5 (CYP3A5), UDP glucuronosyltransferase family 2 member B7 (UGT2B7), ATP binding cassette subfamily B member 1 (ABCB1), ATP binding cassette subfamily C member 3 (ABCC3), solute carrier family 22 member 1 (SLC22A1), opioid receptor kappa 1 (OPRM1), catechol-O-methyltransferase (COMT), and potassium voltage-gated channel subfamily J member 6 (KCNJ6). Treatment guidelines based on genotype are already available only for CYP2D6. SUMMARY The application of PGx in the management of pain with opioids has the potential to improve therapy. We provide a shortlist of 10 genes that are the most promising markers for clinical use in this context.

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Section: Abcb1mentioning

confidence: 96%

Section: Ugt2b7mentioning

confidence: 99%

Analgesia and Opioids: A Pharmacogenetics Shortlist for Implementation in Clinical Practice

et al. 2017

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“…P-glycoprotein (P-gp), the product encoded by ABCB1 gene, is a member of the ATP-binding cassette (ABC) transporter superfamily (Chen et al, 1986). As an ATP-dependent transmembrane efflux pump, it has been closely linked to resistance to substrates including opioids prevented from transporting across the blood-brain barrier to decrease analgesia action in the central nervous system (CNS) (Zhou et al, 2007;Fujita et al, 2010;Fernandez et al, 2012). The pain relief of morphine and fentanyl were much better in P-gp deficient mice than wild type (WT) (Hamabe et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Gene Polymorphisms of OPRM1 A118G and ABCB1 C3435T May Influence Opioid Requirements in Chinese Patients with Cancer Pain

Gong¹,

Wang²,

Liu³

et al. 2013

Asian Pacific Journal of Cancer Prevention

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“…Understanding the mechanisms underlying this variability can help identify susceptible patient populations. Opioid-related adverse events occur in approximately 15% of postoperative patients in the clinical setting (Kessler et al, 2013) and represent a subset of VDRs that may be attenuated by considering altered function of opioid metabolizing enzymes and transporters (Fujita et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Mechanistic Basis of Altered Morphine Disposition in Nonalcoholic Steatohepatitis

Dzierlenga

Clarke

Hargraves

et al. 2014

J Pharmacol Exp Ther

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Morphine is metabolized in humans to morphine-3-glucuronide (M3G) and the pharmacologically active morphine-6-glucuronide (M6G). The hepatobiliary disposition of both metabolites relies upon multidrug resistance-associated proteins Mrp3 and Mrp2, located on the sinusoidal and canalicular membrane, respectively. Nonalcoholic steatohepatitis (NASH), the severe stage of nonalcoholic fatty liver disease, alters xenobiotic metabolizing enzyme and transporter function. The purpose of this study was to determine whether NASH contributes to the large interindividual variability and postoperative adverse events associated with morphine therapy. Male Sprague-Dawley rats were fed a control diet or a methionine-and choline-deficient diet to induce NASH. Radiolabeled morphine (2.5 mg/kg, 30 mCi/kg) was administered intravenously, and plasma and bile (0-150 or 0-240 minutes), liver and kidney, and cumulative urine were analyzed for morphine and M3G. The antinociceptive response to M6G (5 mg/kg) was assessed (0-12 hours) after direct intraperitoneal administration since rats do not produce M6G. NASH caused a net decrease in morphine concentrations in the bile and plasma and a net increase in the M3G/morphine plasma area under the concentration-time curve ratio, consistent with upregulation of UDP-glucuronosyltransferase Ugt2b1. Despite increased systemic exposure to M3G, NASH resulted in decreased biliary excretion and hepatic accumulation of M3G. This shift toward systemic retention is consistent with the mislocalization of canalicular Mrp2 and increased expression of sinusoidal Mrp3 in NASH and may correlate to increased antinociception by M6G. Increased metabolism and altered transporter regulation in NASH provide a mechanistic basis for interindividual variability in morphine disposition that may lead to opioid-related toxicity.

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Association of UGT2B7 and ABCB1 genotypes with morphine-induced adverse drug reactions in Japanese patients with cancer

Abstract: Our findings suggest that pharmacogenetics can be used to predict the risk of morphine-induced adverse events.

Cited by 86 publications

References 31 publications

Analgesia and Opioids: A Pharmacogenetics Shortlist for Implementation in Clinical Practice

Analgesia and Opioids: A Pharmacogenetics Shortlist for Implementation in Clinical Practice

Gene Polymorphisms of OPRM1 A118G and ABCB1 C3435T May Influence Opioid Requirements in Chinese Patients with Cancer Pain

Mechanistic Basis of Altered Morphine Disposition in Nonalcoholic Steatohepatitis

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