ISSN:
0899-0042
Keywords:
β2-agonist drugs
;
sulfotransferase
;
M-form phenolsulfotransferase
;
sulfation
;
isoproterenol
;
metaproterenol
;
terbutaline
;
albuterol
;
salbutamol
;
salmeterol
;
formoterol
;
Chemistry
;
Organic Chemistry
Source:
Wiley InterScience Backfile Collection 1832-2000
Topics:
Chemistry and Pharmacology
Notes:
The β2-receptor agonist class of drugs is metabolized in humans almost exclusively by sulfate conjugation. The objective of this investigation was to determine the influence of chemical structure on the stereoselectivity of the sulfoconjugation of these chiral drugs. The pure enantiomers of six β2-agonists, including those clinically most widely used, were all effectively sulfated both by the cytosol of the human intestine and the recombinant human M-form phenolsulfotransferase (PST). Whereas the apparent Km values (Km,app) for the sulfation of the individual drug enantiomers by the intestinal cytosol varied widely, ranging from 4.8 μM for (S)-isoproterenol to 889 μM for (S)-albuterol, these Km,app values were highly correlated with those obtained with M-PST (correlation coefficient 0.994). In contrast, the M-PST Vmax,app values were similar for all drug enantiomers, ranging from 276 to 914 pmol min-1 mg-1 protein, implying that substrate binding to M-PST by far is the main determinant of the sulfation activity. For isoproterenol, the Km,app for M-PST was 6.1 times higher for the active (R)- than for the inactive (S)-enantiomer. For other β2-agonists, the stereoselectivity decreased towards unity as the Km,app increased. However, for albuterol, containing a hydroxymethyl substituent at the aromatic ring, the stereoselectivity was dramatically reversed, with 10 times higher Km,app for the inactive (S)- than for the active (R)-enantiomer. Chirality 10:800-803, 1998. © 1998 Wiley-Liss, Inc.
Additional Material:
2 Ill.
Type of Medium:
Electronic Resource
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