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 α-globin and sickle β-globin transgenes (SC), and 3) mice with the human α-globin and sickle β-globin transgenes, and homozygous for the murine α-globin and heterozygous for the βmajor-gene knockout (SCKO). In vitro hepatic microsomal incubations were carried out for each substrate, and data were fit to the Michaelis-Menten equation. Morphine formation had a higher Vmax in SCKO microsomes (0.4 ± 0.009 nmol/min · mg; estimate ± S.E.) than controls (0.25 ± 0.007). Morphine-3-glucuronide formation had Vmax estimates of 18.9 ± 0.6, 25.1 ± 0.4, and 27.06 ± 1.1 nmol/min · mg in control, SC, and SCKO microsomes, respectively. The control Vmax for estradiol-3-glucuronide formation was 2-fold greater than in SCKO microsomes. The control Vmax for estradiol 17-glucuronide formation was 3.4- and 2.2-fold greater than in SC and SCKO microsomes. Thus, in vitro metabolism of opioids is altered in SCA mouse models, which may lead to altered clearances of these drugs.
Footnotes
-
↵1 Abbreviations used are: SCA, sickle cell anemia; RBC, red blood cell; UGT, uridine glucuronosyltransferase, human; ugt, uridine glucuronosyltransferase, rodent; P450, cytochrome P450; SC, sickle cell transgenic mice; SCKO, sickle cell-knockout mice; NB, norbuprenorphine; M3G, morphine-3-glucuronide; UDPGA, uridine diphosphoglucuronic acid; G6P, glucose-6-phosphate; HPLC, high-pressure liquid chromatography; ACN, acetonitrile; BG, buprenorphine glucuronide; E3G, estradiol-3-glucuronide; E17G, estradiol-17-glucuronide; EE2, ethynylestradiol; Cl′int, intrinsic clearance of unbound drug.
-
This project was funded partially by National Institutes of Health Grant HL55552 to R.P.H., and the William and Mildred Peters Endowment, Department of Pharmaceutics, University of Minnesota.
-
This work was submitted by S.N. in partial completion of the requirements for the Ph.D. in Pharmaceutics at the University of Minnesota.
- Received March 3, 2003.
- Accepted September 15, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
DMD articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|