STEREOSELECTIVE SULFATE CONJUGATION OF SALBUTAMOL IN HUMANS - COMPARISON OF HEPATIC, INTESTINAL AND PLATELET ACTIVITY

1 The oral bioavailability of the beta2-adrenoceptor agonist salbutamol has been proposed to be stereoselective, presumably due to presystemic sulphate conjugation. In the present study we examined the stereochemistry of the sulphation reaction in vitro using human tissue preparations. 2 Sulphation of salbutamol was studied with partially purified hepatic M and P form phenol sulphotransferases (PSTs), 100,000 g cytosol of jejunal mucosa and platelet homogenate. The cosubstrate PAPS-35 was used as the sulphate donor. The acceptor substrate was either (+)-, (-)- or (+/-)-salbutamol. 3 Sulphation was catalyzed by the M form PST of the liver but not the P form. The sulphation efficiency (V(max)/K(m)) was 11.9-fold greater for the (-)- than for the (+)-enantiomer, due entirely to a lower apparent K(m) for (-)-salbutamol, 103 mum, than for (+)-salbutamol, 1394 mum. 4 Sulphation by the jejunal mucosa (n = 3) was very similar to that of the M form PST with the efficiency being 9.8-fold greater for the (-)-enantiomer and apparent K(m) values 95 mum and 889 mum for (-)- and (+)-salbutamol, respectively. 5 Sulphation by the platelet (n = 3) was also very similar to that of the M form PST with the efficiency being 9.9-fold greater for the (-)-enantiomer and apparent K(m) values 141 mum and 1190 mum for (-)- and (+)-salbutamol, respectively. 6 The sulphation of racemic (+/-)-salbutamol by all three preparations behaved as would be predicted from the individual enantiomers alone, if the enantiomers in the racemic mixture are regarded as two different substrates competing for the same binding site. 7 These findings suggest the potential for large enantioselectivity in the oral bio-availability of salbutamol, with lower blood concentrations of the pharmacologically more active (-)-enantiomer.