title: Pharmacokinetics and metabolism of (R,R)-methoxyfenoterol in rat.
abstract: (R,R)-fenoterol (Fen), a beta(2)-adrenoceptor agonist, is under clinical investigation in the treatment of congestive heart disease. The pharmacokinetics and metabolism of the 4-methoxyphenyl derivative of (R,R)-Fen, (R,R)-MFen, have been determined following intravenous and oral administration to the rat and compared with corresponding results obtained with (R,R)-Fen. Results from the study suggest that (R,R)-MFen can offer pharmacokinetic and metabolic advantages in comparison to an earlier (R,R)-Fen. The oral administration revealed that the net exposure of (R,R)-MFen was about three-fold higher than that of (R,R)-Fen (7.2 versus 2.3 min x nmol ml(-1)), while intravenous administration proved that the clearance was significantly reduced, 48 versus 146 ml min(-1) kg(-1), the T(1/2) was significantly longer, 152.9 versus 108.9 min, and the area under the curve (AUC) was significantly increased, 300 versus 119 min x nmol ml(-1). (R,R)-MFen was primarily cleared by glucuronidation associated with significant presystemic glucuronidation of the compound. After intravenous and oral administration of (R,R)-MFen, (R,R)-Fen and (R,R)-Fen-G were detected in the urine samples indicating that (R,R)-MFen was O-demethylated and subsequently conjugated to (R,R)-Fen-G. The total (R,R)-Fen and (R,R)-Fen-G as a percentage of the dose after intravenous administration was 3.6%, while after oral administration was 0.3%, indicating that only a small fraction of the drug escaped presystemic glucuronidation and was available for O-demethylation. The glucuronidation pattern was confirmed by the results from in vitro studies where incubation of (R,R)-MFen with rat hepatocytes produced (R,R)-MFen-G, (R,R)-Fen and (R,R)-Fen-G, while incubation with rat intestinal microsomes only resulted in the formation of (R,R)-MFen-G.
authors.affiliation: Laboratory of Clinical Investigation, Gerontology Research Center, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA. dsiluk@amg.gda.pl
authors.forename: D
authors.initials: D
authors.lastname: Siluk
authors.forename: D E
authors.initials: DE
authors.lastname: Mager
authors.forename: H S
authors.initials: HS
authors.lastname: Kim
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.forename: A M
authors.initials: AM
authors.lastname: Furimsky
authors.forename: A
authors.initials: A
authors.lastname: Ta
authors.forename: L V
authors.initials: LV
authors.lastname: Iyer
authors.forename: C E
authors.initials: CE
authors.lastname: Green
authors.forename: I W
authors.initials: IW
authors.lastname: Wainer
mesh_terms: D000284:Administration, Oral; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D005280:Fenoterol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000652:urine; D022781:Hepatocytes / Q000378:metabolism; D007275:Injections, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
chemical_list: C550094:methoxyfenoterol; D005280:Fenoterol