Metabolism of Opioids Is Altered in Liver Microsomes of Sickle Cell Transgenic Mice

Abstract

This article is available online at http://dmd.aspetjournals.org ABSTRACT:Pain in sickle cell anemia (SCA) is clinically managed with opioid analgesics. There are reports that SCA patients tolerate high doses of these drugs without adequate pain relief. The current study investigated the in vitro hepatic metabolism of opioids in mouse models of sickle cell anemia, with the hypothesis that higher dose requirements in SCA could be explained by an increased metabolism rate of opioids. Various rodent cytochrome P450 substrates, i.e., buprenorphine and codeine, and rodent uridine glucuronosyltransferase substrates, i.e., morphine, buprenorphine, and estradiol, were studied. The three groups used were: 1) control C57BL mice, 2) mice with the human ␣-globin and sickle ␤-globin transgenes (SC), and 3) mice with the human ␣-globin and sickle ␤-glo-

Characterizing the Effects of Common UDP Glucuronosyltransferase (UGT) 1A6 and UGT1A1 Polymorphisms oncis-andtrans-Resveratrol Glucuronidation

“…Statistical comparison of the parameter estimates (Table 1) was performed with a two-sided t test assuming normal distribution, for which a p value Ͻ0.01 was considered significant (Nagar et al, 2004a). For comparison of glucuronidation velocities among genotyped liver samples, GraphPad Instat was used to conduct one-way analysis of variance (ANOVA), followed by post hoc Tukey's multiple comparison test.…”

Sulfotransferase (SULT) 1A1 Polymorphic Variants *1, *2, and *3 Are Associated with Altered Enzymatic Activity, Cellular Phenotype, and Protein Degradation

“…Parameter estimates were statistically compared using a two-sided t test assuming normal distribution; a p value less than 0.01 was considered significant (Nagar et al, 2004).…”

Pain-related behaviors and neurochemical alterations in mice expressing sickle hemoglobin: modulation by cannabinoids

“…In addition, increased clearance and metabolism of morphine in SCD may contribute to the increased requirement of morphine. 4,6 Cannabinoid receptor agonist ameliorates hyperalgesia in mice expressing HbS…”

“…3 High doses of opioids are required because of altered pharmacokinetics of morphine and increased clearance. [4][5][6] The efficacy of long-term opioid administration is also impaired by the development of opioid tolerance or opioid-induced hyperalgesia (see Table 1 for definitions). Further, chronic opioid use in SCD may lead to adverse effects on peripheral systems, including renal toxicity and acute chest syndrome.…”