Pharmacokinetics and Metabolism of (R,R)-Methoxyfenoterol in Rat

Abstract

1. (R,R)-Fenoterol (Fen), a β₂-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 of the study suggest that (R,R)-MFen can offer pharmacokinetic and metabolic advantages in comparison to an earlier (R,R)-Fen.
2. 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 × 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 × nmol ml^-1.
3. (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.
4. 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.

Keywords: Hepatocytes, liver microsomes, intestinal microsomes, high-performance liquid chromatography (HPLC), mass spectrometry, pharmacokinetics, phase II drug metabolism