Glucuronidation of morphine and six beta 2-sympathomimetics in isolated rat intestinal epithelial cells.
The metabolism of morphine and six beta 2-sympathomimetics (orciprenaline, terbutaline, fenoterol, salbutamol, ritodrine, and bamethan) in isolated rat intestinal epithelial cells was investigated. Only conjugates with glucuronic acid were detected. With regard to observed Vmax values the beta 2-sympathomimetics can be divided in two groups. The three resorcinols (orciprenaline, terbutaline, fenoterol) have a Vmax value comparable to that of morphine (70-230 pmol/min X mg cell protein). The phenolic beta 2-sympathomimetics (salbutamol, ritodrine, bamethan) exhibit a Vmax value comparable to the Vmax value of 1-naphthol (500-1100 pmol/min X mg cell protein). Calculation of intestinal intrinsic (metabolic) clearance and intestinal first pass extraction ratios from Vmax and Kappm values suggests that most of these drugs may undergo substantial intestinal first pass metabolism after oral administration. The glucuronidation of morphine in isolated mucosal cells could be completely inhibited by addition of 1-naphthol (50 microM), salicylamide (5 mM), or fenoterol (5 mM). Glucuronidation of fenoterol could be partially inhibited by 1-naphthol, salicylamide, and morphine. Preliminary data obtained with microsomes suggest that 1-naphthol and morphine are metabolized by different forms of the intestinal microsomal UDP-glucuronosyltransferase. Fenoterol and ritodrine are probably glucuronidated by the form, which also glucuronidates morphine. The results demonstrate that rat intestinal epithelial cells can be used to predict intestinal metabolism of morphine and other drugs at least qualitatively and that phenolic food constituents (e.g. 1-naphthol) and non-prescription drugs (e.g. salicylamide) may affect the intestinal first pass metabolism of morphine and fenoterol.
Koster
A S
AS
Frankhuijzen-Sierevogel
A C
AC
Noordhoek
J
J
D000318:Adrenergic beta-Agonists / Q000378:metabolism*; D000420:Albuterol / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D004386:Duodenum / Q000378:metabolism; D004847:Epithelial Cells; D004848:Epithelium / Q000378:metabolism; D004983:Ethanolamines / Q000378:metabolism; D005280:Fenoterol / Q000378:metabolism; D005965:Glucuronates / Q000096:biosynthesis*; D007413:Intestinal Mucosa / Q000378:metabolism*; D007583:Jejunum / Q000378:metabolism; D008297:Male; D009921:Metaproterenol / Q000378:metabolism; D009020:Morphine / Q000378:metabolism*; D009022:Morphine Derivatives / Q000096:biosynthesis*; D051381:Rats; D011919:Rats, Inbred Strains; D012312:Ritodrine / Q000378:metabolism; D013726:Terbutaline / Q000378:metabolism
D000318:Adrenergic beta-Agonists; D004983:Ethanolamines; D005965:Glucuronates; D009022:Morphine Derivatives; D005280:Fenoterol; D009921:Metaproterenol; D009020:Morphine; D012312:Ritodrine; D013726:Terbutaline; C018108:morphine-3-glucuronide; D000420:Albuterol