Stereoselective urinary excretion of formoterol and its glucuronide conjugate in human

Abstract

Aims Formoterol is an inhaled β 2 -adrenoceptor agonist used as a racemic mixture of the active (R; R)-and inactive (S; S)-enantiomers ( rac -formoterol). Glucuronidation is an important route of metabolism in humans which occurs faster for (S; S)-formoterol in human liver microsomes. The aim of this study was to investigate the stereoselectivity of urinary excretion of formoterol and its glucuronide conjugate after oral dosing with rac -formoterol. Methods Seven nonsmoking volunteers (six males, one female) were included in the study. After an overnight fast, a single 60 µ g oral dose of rac -formoterol fumarate dihydrate was ingested. Urine samples were collected at 1 h intervals for the first 4 h, and at 6, 8, 12 and 24 h after dosing. Formoterol enantiomers were analysed by chiral h.p.l.c. assay and formoterol glucuronides were determined as formoterol enantiomers after enzymatic cleavage with β -glucuronidase. Results The female subject displayed a different pattern of metabolism and statistical analysis was therefore limited to data for the six males. The median (range) of the total urinary excretion of formoterol was 37.8% (20.9-51.2%) of the dose. The medians (ranges) of the amounts of (R; R)-and (S; S)-formoterol and of (R; R)-and (S; S)-formoterol glucuronide excreted were 2.1 (1.0-2.9), 3.5 (2.6-3.8), 21.0 (13.1-31.0) and 10.3 (4.2-14.6)%, respectively, of the dose. Unchanged (S; S)-formoterol excretion was significantly greater than that of unchanged (R; R)-formoterol and (R; R)-formoterol glucuronide excretion was significantly greater than that of (S; S)-formoterol glucuronide. The total RR-formoterol (unchanged drug plus glucuronide) excreted was significantly greater than the total (S; S)-formoterol. Conclusions Our study demonstrates that the urinary excretion of formoterol in male humans after oral administration of rac -formoterol is stereoselective with preferential excretion of the active (R; R)-formoterol as unchanged drug and glucuronide. The different pattern of metabolism in the female subject provides impetus for further studies of the effect of gender on the stereoselective metabolism and pharmacokinetics of formoterol.

A Comparison of the Expression and Metabolizing Activities of Phase I and II Enzymes in Freshly Isolated Human Lung Parenchymal Cells and Cryopreserved Human Hepatocytes

“…The sulfation of salbutamol has been described previously in lung homogenate in vitro (Pacifici et al, 1996) although this particular pathway was shown not to occur after administration of salbutamol to human (Ward et al, 2000). Interestingly, phase II metabolites of formoterol, a compound known to be sulfated and glucuronidated in human (Rosenborg et al, 1999;Zhang et al, 2002) were not consistently observed in these studies. In contrast, the oleate metabolite of budesonide was observed, indicating the presence of an active fatty acid pathway.…”

“…However, the location and relevance of human pulmonary drug metabolism for inhaled medicines is unclear at present; therefore, the aim of the current study was to investigate the drug-metabolizing capability of the human lung. In particular, demonstration of both phase I and II pathways as well as non-P450-mediated metabolism was considered essential, as these pathways are reportedly involved in the metabolism of inhaled therapies such as salbutamol, beclomethasone dipropionate (BDP), budesonide, and formoterol (Jonsson et al, 1995;Pacifici et al, 1996;Tunek et al, 1997;Joyce et al, 1998;Daley-Yates et al, 2001;Zhang et al, 2002). Freshly isolated mixed lung parenchymal cell (LPC) preparations derived from human lung were used to develop an in vitro model of human pulmonary metabolism.…”

Pharmacokinetics of the enantiomers of trans‐tramadol and its active metabolite, trans‐O‐demethyltramadol, in healthy male and female chinese volunteers

“…The enantiomers of M1 glucuronide were determined as the enantiomers of M1 after enzymic cleavage with b-glucuronidase. 7 …”

Chiral HPLC analysis of formoterol stereoisomers and thermodynamic study of their interconversion in aqueous pharmaceutical formulations

“…While the (S,S)-enantiomer increased the levels of the inflammatory cytokine, granulocyte macrophage-colony stimulating factor (GM-CSF) in human airway smooth muscle cells, the production of GM-CSF was decreased by (R,R)-enantiomer to about 40% of the control [13]. Other dissimilarity in biological activity was in urinary excretion of formoterol enantiomers and their glucuronide conjugates in male subjects, which was found to be stereoselective after oral administration of the racemic (R,R/S,S)-formoterol [14]. The (R,R)-formoterol glucuronide excretion was significantly higher than (S,S)-formoterol glucuronide (59.6% vs. 26.0% of the dose), and vice versa for the unchanged (S,S)-and (R,R)-formoterol (9.5% vs. 5.1% of the dose) [14].…”