Metabolism of a Thiazole Benzenesulfonamide Derivative, a Potent and Selective Agonist of the Human β₃-Adrenergic Receptor, in Rats: Identification of a Novel Isethionic Acid Conjugate

Abstract

(1) is a potent and selective agonist of the human ␤ 3 -adrenergic receptor. We report herein the data from studies of the metabolism and excretion of 1 in rats. Five metabolites were identified in the bile of male SpragueDawley rats administered 3 H-labeled 1 by either oral gavage (10 mg/kg) or intravenous injection (3 mg/kg). These included a pyridine N-oxide derivative (M2), a primary amine resulting from N-dealkylation and loss of the pyridinyl-2-hydroxyethyl group (M4), a carboxylic acid derived from N-dealkylation and loss of the pyridyl-2-hydroxyethyl amine (M5), and the corresponding taurine and isethionic acid conjugates (M1 and M3). Metabolites M1 and M3 also were identified in rats treated with M5 and were generated in incubations of M5 with rat liver subcellular fractions in the presence of ATP and coenzyme A with supplementary taurine or isethionic acid. These results suggest that M5 is the precursor of M1 and M3 and that the formation of these conjugated metabolites follows similar mechanisms of amino acid conjugation. On the other hand, M2, M4, and M5 were produced from 1 in an NADPHdependent manner in incubations with liver microsomes from rats, dogs, monkeys, and humans. In human liver preparations, these routes of biotransformation were shown to be catalyzed by cytochrome P450 3A4. In a bidirectional transport assay, transport of 1 across a monolayer of cells expressing P-glycoprotein (Pgp) was observed to be similar to that of vinblastine, which is an established substrate of the transporter protein. This finding, together with the observation that the parent compound was excreted in the feces of bile duct-cannulated animals following intravenous dosing, suggests that 1 is subject to Pgp-mediated excretion from intestine of rats.Increased concerns in the United States and in many other countries have been focused on obesity, which in many cases is the prelude to developing more severe disorders such as Type II diabetes, hypertension, and cardiovascular diseases (Eckel and Krauss, 1998;Wickelgren, 1998). Obesity is the result of an imbalance between caloric intake and energy expenditure; excess energy is therefore accumulated in the form of triglycerides in adipocytes, and this accumulation increases with the expansion of adipose tissues. In general, mechanisms for treatment of obesity include increasing energy consumption, stimulating fat metabolism, and reducing nutrient intake (Campfield et al., 1998;Kordik and Reitz, 1999). The discovery of a unique ␤-adrenergic receptor subtype, namely the ␤3 receptor, on the surface of adipocytes that stimulates lipolysis has led to speculation that a selective agonist of the ␤ 3 -adrenergic receptor may be used for treating obesity (Danforth and Himms-Hagen, 1997;Weyer et al., 1999). In experimental animals, treatment with agonists of the ␤ 3 -adrenergic receptor led to increases in metabolic rate, weight loss, and improved glucose tolerance (Bloom et al., 1992;Cawthorne et al., 1992). Similar studies in human trials, however, were inconclusive, and res...

Metabolism of prazosin in rat and characterization of metabolites in plasma, urine, faeces, brain and bile using liquid chromatography/mass spectrometry (LC/MS)

“…The taurine conjugate, M19, was detected in bile and is likely derived from M7 which contains an aliphatic carboxylic acid that is available for conjugation with taurine. Carboxylic acid containing drugs, such as, diclofenac (Stierlin et al 1979) or metabolites (Tang et al 2002) can become conjugated with taurine.…”

The Pharmacokinetics of a Thiazole Benzenesulfonamide β3-Adrenergic Receptor Agonist and Its Analogs in Rats, Dogs, and Monkeys: Improving Oral Bioavailability

“…dose into the feces of bile duct-cannulated rats suggested that 1 underwent efflux from the gastrointestinal tract. Since 1 has been identified as a substrate for P-glycoprotein (Tang et al, 2002), it is likely that efflux into the gastrointestinal tract was mediated by this transporter.…”

“…The metabolite profile was determined in bile collected from rats dosed orally with 1. The metabolites that were identified were primarily hepatic oxidation products and included the pyridine N-oxide derivative, a primary amine resulting from N-dealkylation and loss of the pyridinyl-2-hydroxyethyl group; a carboxylic acid derived from N-dealkylation and loss of pyridinyl-2-hydroxyethylamine; and the corresponding taurine and isoethionic acid conjugates (Tang et al, 2002).…”

Species Differences in Metabolism and Pharmacokinetics of a Sphingosine-1-Phosphate Receptor Agonist in Rats and Dogs: Formation of a Unique Glutathione Adduct in the Rat

“…In general, taurine conjugation is perceived to be a high-affinity, low-capacity system (Mulder, 1990), whereas conjugation with glucuronic acid is considered to be a highcapacity process with broad substrate specificity (Hutt and Caldwell, 1990). In the case of a ␤ 3 -adrenergic receptor agonist, Tang et al (2002) postulated that preferential conjugation by taurine or isethionic acid was observed as a result of the limited availability of the precursor carboxylic acid metabolite. In their study, direct in vivo administration of the carboxylic acid metabolite to rats at higher concentrations led to a combination of amino acid and glucuronic acid conjugation.…”