Stereoselective sulphate conjugation of racemic terbutaline by human liver cytosol.

Abstract

1. The enantioselectivity of the sulphation of racemic terbutaline by phenolsulphotransferases was examined in vitro using cytosol from human livers (n = 3) and [35S]‐3′‐phosphoadenosine‐5′‐phosphosulphate (PAP35S) as the sulphate donor. 2. The radioactive sulphate conjugate formed was isolated by h.p.l.c. and its enantiomers were separated intact by h.p.l.c. after chiral derivatization. 3. Sulphation of racemic terbutaline occurred with the same apparent Km value for both enantiomers (270 microM). The extent of sulphation of the (+)‐ enantiomer was double that of the (‐)‐enantiomer, solely due to a difference in their apparent Vmax values. 4. Sulphation of racemic prenalterol, a structural analogue of terbutaline, also showed a two‐ fold preference for the (+)‐enantiomer. 5. These findings suggest that enantioselective sulphate conjugation of chiral phenolic sympathomimetic amine drugs may lead to enantioselective pharmacokinetics that should be considered in the clinical use of these drugs.

Enantioselective sulfation of ?2-receptor agonists by the human intestine and the recombinant M-form phenolsulfotransferase

“…However, similar to a previous report, 6 terbutaline seems to show a significant stereochemical difference also in the V max,app value, which contributes to the overall stereoselectivity in the sulfation of this drug. For albuterol and salmeterol the situation is different.…”

“…4,5 Recent human studies have demonstrated in vitro stereoselectivity in the sulfate conjugation pathway for several ␤ 2 -agonist drugs. [6][7][8][9][10][11][12] The stereoselective oral dose pharmacokinetics observed for two of these drugs, i.e., terbutaline 13 and albuterol, 14 is likely due to stereoselective sulfation in the intestine. Overall, these in vitro/in vivo studies indicate that stereoselective metabolism can either enhance or diminish the plasma concentrations of the active enantiomer relative to the inactive form.…”

Stereoselective glucuronidation of formoterol by human liver microsomes

“…The stereoselectivity of glucuronidation of formoterol was mainly due to an enantiomeric difference in V max . In comparison with other β 2 ‐adrenoceptor agonists, the stereochemical pattern of formoterol metabolism is similar to that for terbutaline [5] but opposite to that for salbutamol [6] both of which occur by sulphation in humans. Like formoterol, terbutaline stereoselectivity mainly results from a difference in V max but for salbutamol, where metabolism involves a preference for the (R)‐enantiomer, stereoselectivity mainly arises from an enantiomeric difference in K m .…”

“…The drugs are marketed as racemic mixtures although only the R‐enantiomers are pharmacologically active [2]. A number of in vivo and in vitro studies has shown that the metabolism of β 2 ‐adrenoceptor agonists is stereoselective [3–7]. This has important consequences in the oral delivery of these drugs since they are subject to extensive first pass metabolism [3, 8].…”

Sympathomimetic enantiomers and asthma

“…It has been established that there is selective elimination of Rsalbutamol from human plasma, 87,88 as a result of its stereoselective sulphate conjugation, since the phenol sulphotransferases that are responsible for presystemic sulphoconjugation show a 10-fold preference for R-salbutamol over S-salbutamol. 89,90 A proportionate reduction of the ratio of R-salbutamol to S-salbutamol parallels the progres- sive loss of protective efficacy and provides a rationale for the delayed onset of this phenomenon.…”