Stereoselective formation of fenoterol-para-glucuronide and fenoterol-meta-glucuronide in rat hepatocytes and enterocytes

• Published in: Biochemical pharmacology Vol. 35; no. 12; p. 1981
• Main Authors: Koster, A S, Frankhuijzen-Sierevogel, A C, Mentrup, A
• Format: Journal Article
• Language: English
• Published: England 15.06.1986
• Subjects: Animals; Fenoterol - analogs & derivatives; Fenoterol - metabolism; In Vitro Techniques; Intestinal Mucosa - metabolism; Kinetics; Liver - metabolism; Male; Metabolic Clearance Rate; Rats; Rats, Inbred Strains; Stereoisomerism
• ISSN: 0006-2952
• DOI: 10.1016/0006-2952(86)90730-6

The glucuronidation of fenoterol (Berotec, Partusisten) in isolated rat hepatocytes and enterocytes was investigated. Two different glucuronides, fenoterol para-glucuronide and fenoterol meta-glucuronide, were formed in proportions, that were constant over the concentration range investigated (0-1 mM). The fraction of para-glucuronide formed was 0.40 +/- 0.01 for hepatocytes and 0.54 +/- 0.01 for enterocytes. Fenoterol consists of a racemic mixture of SS'(+)fenoterol and RR'(-)fenoterol. The maximum glucuronidation rate of the (-)enantiomer (Vmax = 3.6 +/- 0.3 nmol/min/mg in hepatic microsomes and 3.4 +/- 0.1 nmol/min/mg in intestinal microsomes) is significantly lower than the same values of the (+)isomer (Vmax = 6.7 +/- 0.8 nmol/min/mg in hepatic microsomes and 5.8 +/- 0.4 nmol/min/mg in intestinal microsomes). Kmapp-values for the (-)enantiomer were lower than for the (+)enantiomer. Similar, but less pronounced, differences in Vmax were observed in isolated cells: Vmax = 148 +/- 13 and 372 +/- 50 pmol/min/mg [(-)fenoterol in hepatocytes and enterocytes], Vmax = 173 +/- 12 and 444 +/- 57 pmol/min/mg [(+)fenoterol in hepatocytes and enterocytes]. Calculation of intrinsic metabolic clearance (Clint = Vmax/Kmapp) from the cellular data suggests that the (+)enantiomer may be more efficiently eliminated by liver metabolism in vivo than the (-)enantiomer. This can result in stereoselective first-pass metabolism of the fenoterol enantiomers.