Enantioselective disposition of albuterol in humans. 1996

D W Boulton, and J P Fawcett
School of Pharmacy, University of Otago, Dunedin, New Zealand.

The study of enantioselective disposition of chiral drugs is important to provide a rationale of plasma concentration-effect relationships, which are often misleading when based on total drug concentration. It is also important when considering new dosage routes or formulations in order to optimize therapeutic plasma concentrations of the active enantiomer. Improvements in the sensitivity and selectivity of biological assays coupled with the developments in chiral analysis have made it possible to study the enantioselective disposition of drugs. Although valuable pharmacokinetic data were obtained for the beta 2-agonists by nonenantioselective methodology, more recent chiral studies have revealed the existence of extensive enantioselectivity in the disposition of these agents. The most significant features of the enantioselective disposition of albuterol are the relatively rapid plasma clearance and low bioavailability of the eutomer. Although this in itself does not necessarily justify the development of a single enantiomer formulation, the implications of the high levels of distomer after i.v. and oral dosing await clarification. Similarly, more work is required to elucidate the consequences of the major difference in disposition between albuterol and terbutaline in humans through both in vivo and in vitro studies of the mechanisms giving rise to this phenomenon. The enantioselective disposition of the other clinically used beta 2-agonists, such as fenoterol, formoterol, and salmeterol also needs to be characterized. The metabolism of the majority of beta 2-agonists is generally by conjugation to give one major metabolite. The situation is therefore uncomplicated by multiple metabolic pathways, which may differ in the extent and direction of their enantioselectivity. Many beta 2-agonists are excreted largely unchanged in the urine making studies of urinary excretion accessible without the requirement for very sensitive assays. The realization that the enantiomers of beta 2-agonists previously thought of as "inactive" may be associated with toxic effects is a further compelling reason to study the enantioselective pharmacokinetics of this class of drugs. In addition, the role of enantiomers in producing side effects, such as tremor and reduction in renal function, needs to be reassessed. The beta 2-agonists can be looked on as textbook examples of the inherent danger of ignoring chirality in the study of pharmacokinetics and pharmacodynamics. The growing body of information on the enantioselective disposition of beta 2-agonists in humans will enhance the rational use of these drugs in the future management of patients.

UI MeSH Term Description Entries
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000420 Albuterol A short-acting beta-2 adrenergic agonist that is primarily used as a bronchodilator agent to treat ASTHMA. Albuterol is prepared as a racemic mixture of R(-) and S(+) stereoisomers. The stereospecific preparation of R(-) isomer of albuterol is referred to as levalbuterol. Salbutamol,2-t-Butylamino-1-(4-hydroxy-3-hydroxy-3-hydroxymethyl)phenylethanol,Albuterol Sulfate,Proventil,Sultanol,Ventolin
D001673 Biodegradation, Environmental Elimination of ENVIRONMENTAL POLLUTANTS; PESTICIDES and other waste using living organisms, usually involving intervention of environmental or sanitation engineers. Bioremediation,Phytoremediation,Natural Attenuation, Pollution,Environmental Biodegradation,Pollution Natural Attenuation
D013237 Stereoisomerism The phenomenon whereby compounds whose molecules have the same number and kind of atoms and the same atomic arrangement, but differ in their spatial relationships. (From McGraw-Hill Dictionary of Scientific and Technical Terms, 5th ed) Molecular Stereochemistry,Stereoisomers,Stereochemistry, Molecular,Stereoisomer

Related Publications

D W Boulton, and J P Fawcett
October 1991, Antimicrobial agents and chemotherapy,
D W Boulton, and J P Fawcett
June 2014, Drug testing and analysis,
D W Boulton, and J P Fawcett
April 1996, British journal of clinical pharmacology,
D W Boulton, and J P Fawcett
January 1996, Clinical reviews in allergy & immunology,
D W Boulton, and J P Fawcett
May 2014, Biopharmaceutics & drug disposition,
D W Boulton, and J P Fawcett
June 2003, Clinical chemistry,
D W Boulton, and J P Fawcett
June 1997, Antimicrobial agents and chemotherapy,
D W Boulton, and J P Fawcett
January 1994, Chirality,
D W Boulton, and J P Fawcett
February 1988, Journal of pharmaceutical sciences,
D W Boulton, and J P Fawcett
December 1989, Anesthesia and analgesia,
Copied contents to your clipboard!