(-)-Salbutamol sulphation in the human liver and duodenal mucosa : interindividual variability

Abstract

1. Salbutamol as a beta 2-adrenergic agonist used in the treatment of lung obstructive disease and premature labour. It has a bioavailability of 50% and sulphation is the main route of its metabolism. (-)-Salbutamol retains most of the beta 2-adrenergic activity and, thereby, we describe the interindividual variability in the sulphation rate of (-)-salbutamol in 100 specimens of human liver and duodenal mucosa. 2. The mean rate (pmol/min/mg of salbutamol sulphation was 498 in the duodenum and 141 in the liver with 4-fold variation within +/-2 SD units in both tissues. 3. A modelling approach based on the comparison of the best fittings obtained using a gaussian and the sum of two gaussian curves revealed the presence of two subgroups in the hepatic rate of salbutamol sulphation and their means were 69.5 and 105 pmol/min/mg (p < 0.05). In the duodenum, the rate of salbutamol sulphation approached normality. 4. The rates of salbutamol and 4-nitrophenol sulphation correlated highly (r = 0.853; p < 0.001) in the liver whereas in duodenum the rates of salbutamol and dopamine correlated highly (r = 0.914; p < 0.001), 4-Nitrophenol and dopamine are the diagnostic substrates of phenol- and catechol-sulphotransferases respectively. These findings are consistent with the view that the rate of salbutamol sulphation is higher in the gut than in liver and it varies considerably in both tissues.

Prediction of Human Drug Clearance by Multiple Metabolic Pathways: Integration of Hepatic and Intestinal Microsomal and Cytosolic Data

“…Published in vitro sulfation studies (Walle et al, 1993;Pacifici et al, 1997;Honma et al, 2002) generally focus on activity data rather than on full kinetic characterization; this is particularly evident with intestinal cytosolic studies. Reported studies show large variations in experimental conditions, including concentration of human cytosolic protein, concentration of the cofactor PAPS, buffer type, and pH range.…”

Testosterone sulphation and glucuronidation in the human liver: interindividual variability

“…Interindividual variability of sulphotransferase has been investigated fairly extensively and studies on ethinyloestradiol (3), desipramine (4), dopamine and 4-nitrophenol (5), minoxidil (6) and salbutamol (7) have shown a 7-fold variation and a lack of gender regulation. Preliminary.…”

The Pharmacogenetics of Asthma Therapy

“…Furthermore, each of these therapeutic medications demonstrate marked inter-individual variability in drug metabolism, suggesting that genetics may play a role. In fact, in one study of the metabolism of the widely-prescribed 2 -agonist albuterol (salbutamol), a classic bimodal peak in the rate of hepatic sulphation was noted (mean sulphation rates of 69.5 and 105 pmol/min/mg (p < 0.05)) [38]. Additionally, while it may be argued that systemic pharmacokinetics has little to do with inter-individual variation in response at the level of the therapeutic target, given that these medications are administered primarily through inhalation, a large percentage (~40-90%) of drugs administered through metered dose inhalers is swallowed and available for systemic absorption [42].…”

“…All three of these types of asthma treatments are metabolized in the liver by well-known mechanisms; the 2 -agonists undergo sulphate conjugation [37,38], while both leukotriene antagonists and corticosteroids use the cytochrome p450 system for a significant portion of their metabolism [39][40][41]. Furthermore, each of these therapeutic medications demonstrate marked inter-individual variability in drug metabolism, suggesting that genetics may play a role.…”