BIOTRANSFORMATION OF A GABA<sub>A</sub>RECEPTOR PARTIAL AGONIST IN SPRAGUE-DAWLEY RATS AND CYNOMOLGUS MONKEYS: IDENTIFICATION OF TWO UNIQUE<i>N</i>-CARBAMOYL METABOLITES

Shaffer, Christopher L.; Gunduz, Mithat; O’Connell, Thomas N.; Obach, R. Scott; Yee, Shiyin

doi:10.1124/dmd.105.004630

Cited by 30 publications

(33 citation statements)

References 24 publications

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“…Active renal secretion of 1 was observed as its unbound CL R was 6-fold greater than the glomerular filtration rate (GFR) ( Table 3), consistent with the identification of 1 as a multidrug resistance 1 P-glycoprotein substrate (Venkatakrishnan et al, 2007) and the established contribution of this transporter to active renal secretion of its substrates (Lee and Kim, 2004). A similar extent of active renal secretion was observed in monkeys (6ϫ GFR) but not rats (2ϫ GFR) (Shaffer et al, 2005).…”

Section: Discussionsupporting

confidence: 58%

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Metabolism and Disposition of a γ-Aminobutyric Acid Type A Receptor Partial Agonist in Humans

Shaffer¹,

Gunduz²,

Vaz³

et al. 2008

Drug Metab Dispos

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Section: Discussionsupporting

confidence: 58%

“…However, the size of this contribution was undeterminable because it was unknown how much of 1 (if any) detected in feces was actually absorbed following ingestion. Biliary clearance of 1 was minimal in both rats and monkeys (Shaffer et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Metabolism and Disposition of a γ-Aminobutyric Acid Type A Receptor Partial Agonist in Humans

Shaffer¹,

Gunduz²,

Vaz³

et al. 2008

Drug Metab Dispos

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“…7, A and B), which confirmed that M24 was a glucuronide metabolite. Although the carbamic acid intermediate was not observed in the incubation mixture by LC/MS/MS because of the instability of this species (Shaffer et al, 2005;Gunduz et al, 2010), the fragmentation of M24 has the signature fragmentation pattern of N-carbamoyl glucuronides, which produced the product ion of m/z 413, 44 Da higher than the parent drug (Dow et al, 1994;Liu et al, 2001;Shaffer et al, 2005;Gunduz et al, 2010). The exact mass measurement confirmed that M24 is a carbamoyl glucuronide of C and D).…”

Section: Disposition Of Bms-690514 In Rats Dogs and Rabbitsmentioning

confidence: 85%

Metabolism and Disposition of [¹⁴C]BMS-690514 after Oral Administration to Rats, Rabbits, and Dogs

Hong

Su²,

Sun³

et al. 2010

Drug Metab Dispos

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]BMS-690514 to rats and dogs, the majority of the radioactive dose (61-71%) was recovered in the feces, whereas 18 to 20% was eliminated in urine. In bile duct-cannulated rats, 83 and 17% of the administered radioactivity was recovered in the bile and urine, respectively, suggesting that biliary secretion was a major route for the elimination of BMS-690514-derived radioactivity in rats.The parent compound underwent extensive metabolism in both species, with <12% of the administered radioactivity recovered as BMS-690514 in the excreta samples. Metabolite profiles in plasma were qualitatively similar in rats, rabbits, and dogs. Unchanged BMS-690514 was a prominent drug-related component in the plasma profiles from all the species. However, multiple metabolites contributed significantly to the circulating radioactivity, particularly for rabbit and dog, in which metabolites comprised 73 to 93% of the area under the time curve (0-8 h). Circulating metabolites included M6, a direct Oglucuronide conjugate; M1, a hydroxylated metabolite; and glucuronide conjugates of hydroxylated and O-demethylated metabolites. Overall, the results from these studies suggested that BMS-690514 was well absorbed and highly metabolized through multiple pathways in these preclinical species.

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“…17) It has been proposed that the mechanism that generates these glucuronides starts by forming carbamic acid as an intermediate under physiological conditions in the liver through a reversible reaction with CO 2 dissolved in the environmental fluid. 13,[18][19][20][21][22] UDP-glucuronyl transferase (UGT) then causes the immediate conjugation of this carbamic acid with glucuronic acid by utilizing UDPglucuronic acid as a cofactor. Recent studies using recombinant human enzymes suggest that UGT2B7, UGT1A3, UGT2B4, and UGT1A6 may be the UGT isozymes responsible for the formation of sertraline carbamoyl glucuronide, 21) and UGT2B7 for the formation of varenicline carbamoyl glucuronide.…”

Section: Discussionmentioning

confidence: 99%

“…This is probably due to the slow rotation of the carbonyl glucuronic acid moiety at the C-N bond of the carbamate. 13) An overview of the postulated metabolic pathways of this drug in mice is shown in Fig. 4.…”

Section: Identification Of An Unknown Biliary Metabolitementioning

confidence: 99%

Pharmacokinetics and Metabolism of an .ALPHA.,.BETA.-Blocker, Amosulalol Hydrochloride, in Mice: Biliary Excretion of Carbamoyl Glucuronide

Suzuki

Kamimura

2007

Biological & Pharmaceutical Bulletin

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Amosulalol hydrochloride is a combined a-and b-blocker that was selected from a series of sulphonamide-substituted phenylethylamines. It blocks both postsynaptic a 1 -and b 1 -adrenoceptors to almost the same extent. When administered to conscious, spontaneously hypertensive rats, it reduces blood pressure via its a 1 -blocking activity without causing reflex tachycardia because of its b 1 -blocking action.1) This drug exhibited dose-dependent hypotensive effects in healthy volunteers, 2) and is used for the treatment of essential hypertension.3) In contrast to a structurally related a-and bblocker, labetalol, 4) amosulalol's first-pass metabolism was almost negligible in humans.2) However, this drug was extensively metabolized in laboratory animals 5) yielding an order of total body clearance as follows: rats>dogs>monkeys>hu-mans. 2,6) The metabolites found in these animals were derived through the hydroxylation (M-1, M-3, M-4), demethylation (M-2), and oxidative cleavage of the C-N bond (M-5). Some of them were subsequently conjugated to their glucuronides or sulfates. In humans, only the sulfate of M-3 was quantified as the urinary metabolite. 7) In the present study, pharmacokinetic and metabolic studies of amosulalol hydrochloride in mice were undertaken, with amosulalol carbamoyl glucuronide being reported as a new amosulalol metabolite found in bile. MATERIALS AND METHODS ChemicalsAmosulalol hydrochloride and its metabolites, M-1, M-2, M-3, M-4 and M-6 (desmethyl metabolite at o-methoxyphenoxy group of M-1), were supplied by the Chemistry Laboratories of Astellas Pharma Inc. (Ibaraki, Japan). M-5 (o-methoxyphenoxy acetic acid) was purchased from Tokyo Kasei (Tokyo, Japan). 14 C-Amosulalol hydrochloride, labelled at both of the carbons in the ethyl group of the o-methoxyphenoxy ethyl moiety, was synthesized in our laboratories.8) All other reagents were of analytical grade. Animal Studies Male ICR mice (4-7 weeks) were purchased from Charles River Laboratories Japan or CLEA Japan, and used after a one-week period of acclimatization.Amosulalol hydrochloride was administered intravenously as a solution in saline and orally as an aqueous solution. Mice were fasted overnight before oral administration, and fed 4 h after dosing. Blood samples were taken from the inferior vena cava with heparinized syringes under diethyl ether anesthesia, and each animal was sacrificed at each sampling point. For urine and fecal sample collection, animals were kept in glass metabolic cages for 24 or 48 h after dosing. For the metabolite identification, bile samples were obtained from bile duct-cannulated mice during hours 0 and 24 after dosing. This research was conducted in accordance with the "Principles of Laboratory Animal Care" (NIH publication #85-23, revised 1985).Determination of Radioactivity The urine collected was diluted 10-fold with distilled water. Aquaol-2 (10 ml, New England Nuclear) was then added to a 0.1-ml aliquot of the diluted sample. In addition, about 100 mg of dried feces was combusted in a sample oxidiz...

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BIOTRANSFORMATION OF A GABA_ARECEPTOR PARTIAL AGONIST IN SPRAGUE-DAWLEY RATS AND CYNOMOLGUS MONKEYS: IDENTIFICATION OF TWO UNIQUEN-CARBAMOYL METABOLITES

Cited by 30 publications

References 24 publications

Metabolism and Disposition of a γ-Aminobutyric Acid Type A Receptor Partial Agonist in Humans

Metabolism and Disposition of a γ-Aminobutyric Acid Type A Receptor Partial Agonist in Humans

Metabolism and Disposition of [¹⁴C]BMS-690514 after Oral Administration to Rats, Rabbits, and Dogs

Pharmacokinetics and Metabolism of an .ALPHA.,.BETA.-Blocker, Amosulalol Hydrochloride, in Mice: Biliary Excretion of Carbamoyl Glucuronide

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BIOTRANSFORMATION OF A GABAARECEPTOR PARTIAL AGONIST IN SPRAGUE-DAWLEY RATS AND CYNOMOLGUS MONKEYS: IDENTIFICATION OF TWO UNIQUEN-CARBAMOYL METABOLITES

Cited by 30 publications

References 24 publications

Metabolism and Disposition of a γ-Aminobutyric Acid Type A Receptor Partial Agonist in Humans

Metabolism and Disposition of a γ-Aminobutyric Acid Type A Receptor Partial Agonist in Humans

Metabolism and Disposition of [14C]BMS-690514 after Oral Administration to Rats, Rabbits, and Dogs

Pharmacokinetics and Metabolism of an .ALPHA.,.BETA.-Blocker, Amosulalol Hydrochloride, in Mice: Biliary Excretion of Carbamoyl Glucuronide

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BIOTRANSFORMATION OF A GABA_ARECEPTOR PARTIAL AGONIST IN SPRAGUE-DAWLEY RATS AND CYNOMOLGUS MONKEYS: IDENTIFICATION OF TWO UNIQUEN-CARBAMOYL METABOLITES

Metabolism and Disposition of [¹⁴C]BMS-690514 after Oral Administration to Rats, Rabbits, and Dogs