Metabolism and Disposition of Novel Des-Fluoro Quinolone Garenoxacin in Experimental Animals and an Interspecies Scaling of Pharmacokinetic Parameters

Hayakawa, Hiroyoshi; Fukushima, Yoko; Katô, Hiroshi; Fukumoto, Hiroyuki; Kadota, Takumi; Yamamoto, Hiroyuki; Kuroiwa, Hiroyuki; Nishigaki, Junko; Tsuji, Akira

doi:10.1124/dmd.31.11.1409

Cited by 33 publications

(20 citation statements)

References 21 publications

(19 reference statements)

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“…It was reported that N-carbamoylation proceeded through a stable carbamic acid interme- diate that could be isolated from plasma. Such other stable carbamic acid was reported by Hayakawa et al (2003) for garenoxacin in rat and monkey bile and in dog feces and for metoclopramide in our laboratory .…”

Section: Carbamoyl Glucuronidesmentioning

confidence: 79%

“…N-Carbamoyl glucuronide conjugate of varenicline was identified in plasma and urine of rat, monkey, and human, but not mouse (Obach et al, 2006). Garenoxacin-N-carbamoyl glucuronide was detected in multiple species: rat and monkey bile and dog urine and feces (Hayakawa et al, 2003). Tocainide-N-carbamoyl glucuronide has been reported to be present in urine of guinea pig, dog, cat, and rabbit (Gipple et al, 1982).…”

Section: Carbamoyl Glucuronidesmentioning

confidence: 95%

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Unusual Glucuronides

Argikar¹

2012

Drug Metab Dispos

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ABSTRACT:Glucuronidation reaction is catalyzed by mammalian uridine diphosphoglucuronosyl transferases by using uridine diphosphoglucuronic acid as a cosubstrate. Conjugation of glucuronic acid to nucleophilic functional groups in chemical entities results in formation of glucuronides. As anticipated, a number of nucleophilic functional groups such as hydroxyl, phenolic, acyl, primary secondary and tertiary amino, etc. in a diverse set of chemical compounds are known to form the corresponding glucuronides. Glucuronides have been reported to be formed at carbon atoms, selenium atoms, and upon N-carbamoylation of primary and secondary amino groups. Glucuronides are also believed to be the end products of metabolism. However, there are examples where glucuronidation results in further oxidative or conjugative biotransformation reactions. The objective of this review is to highlight unusual glucuronide conjugates. Diglucuronide conjugates reported in the literature fall under two distinct categories. Use of prefixes such as "bis" versus "di" has been previously proposed for separating the two types of diglucuronides. In spite of this, literature reports for diconjugative glucuronide metabolites reflect interchangeable use of "bisglucuronides" and "diglucuronides." Furthermore, the application of such prefixes does not adhere to recommendations of International Union of Pure and Applied Chemistry nomenclature for substituent groups. Therefore, an effort is made in this review to document the historic reports for diglucuronides into two distinct types for sake of clarity and to allow differentiation between the two types of diconjugative metabolites. Overall, this commentary centers on unusual glucuronide metabolites that result from conjugation at uncommon functional groups, glucuronides undergoing ensuing oxidative or conjugative metabolic transformations. Structural and mechanistic aspects are also discussed.

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Section: Carbamoyl Glucuronidesmentioning

confidence: 79%

Section: Carbamoyl Glucuronidesmentioning

confidence: 95%

Unusual Glucuronides

Argikar¹

2012

Drug Metab Dispos

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“…Carbamic acid derivatives of piperazine (Kirsch et al, 2000) and des-methyl org1377 (Delbressine et al, 1990) were identified in this manner, generated after reaction of NaHCO 3 with respective parent molecules. However, stable carbamic acids have also been reported by Shaffer et al (2005) and Hayakawa et al (2003). A trans-esterification type reaction has been used as a method of trapping an unstable N-Carbamoyl glucuronides of unstable carbamic acids can convert back to parent moieties upon hydrolysis (Tremaine et al, 1989) or even during sample preparation.…”

Section: Discussionmentioning

confidence: 99%

Identification of a NovelN-Carbamoyl Glucuronide: In Vitro, In Vivo, and Mechanistic Studies

Gunduz

Argikar

Baeschlin³

et al. 2009

Drug Metab Dispos

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ABSTRACT:1-[4-Aminomethyl-4-(3-chlorophenyl)-cyclohexyl]-tetrahydro-pyrimidin-2-one, 1, was developed as an inhibitor of dipeptidyl peptidase-4 enzyme. Biotransformation studies with 1 revealed the presence of an N-carbamoyl glucuronide metabolite (M1) in rat bile and urine. N-Carbamoyl glucuronides are rarely observed, and little is understood regarding the mechanism of N-carbamoyl glucuronidation. The objectives of the current investigation were to elucidate the structure of the novel N-carbamoyl glucuronide, to investigate the mechanism of N-carbamoyl glucuronide formation in vitro using stable labeled CO 2 , UDP glucuronosyltransferase (UGT) reaction phenotyping, and to assess whether M1 was formed to the same extent in vitro across species-mouse, rat, hamster, dog, monkey, and human. Structure elucidation was performed on a mass spectrometer with accurate mass measurement and MS n capabilities.13 C-labeled carbon dioxide was used for identification of the mechanism of N-carbamoyl glucuronidation. Mechanistic studies with 13 C-labeled CO 2 in rat liver microsomes revealed that CO 2 from the bicarbonate buffer (in equilibrium with exogenous CO 2 ) may be responsible for the formation of M1. M1 was formed in vitro in liver microsomes from multiple species, mainly rat and hamster, followed by similar formation in dog, monkey, mouse, and human. M1 could be detected in UGT1A1, UGT1A3, and UGT2B7 Supersomes in a CO 2 -rich environment. In conclusion, our study demonstrates that formation of M1 was observed in microsomal incubations across various species and strongly suggests incorporation of CO 2 from the bicarbonate buffer, in equilibrium with exogenous CO 2 , into the carbamoyl moiety of the formed N-carbamoyl glucuronide.

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“…This includes, RP-HPLC 2 method for assay, metabolism and deposition study in rats, monkey and dog 3 , joint cartilage study in immature rats …”

Section: Introductionmentioning

confidence: 99%

Solid Phase Extraction-HPLC Method for Determination and Pharmacokinetic Study of Garenoxacin in Rat Plasma after Oral Administration

Kakde¹,

Warthi²,

Chilbule³

2017

IJPTR

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:A method based on solid phase extraction was developed for the determination of Garenoxacin in rat plasma after oral administration by high-performance liquid chromatography coupled with PDA detection (HPLC-PDA). Variables parameter affecting the solid phase extraction efficiency were evaluated and optimized. Chromatography separation was performed on a THERMO, BDS HYERSIL C18 column (4.6 mm × 100mm, 5µ) by isocratic elution with PDA detection at 279 nm. The assay was linear over the range of 15-44 μg/ml and the lower limit of quantification (LLOQ) was 15 μg/ml. The extraction recoveries were more than 77 %, the accuracies were within 3.97%, and the intra-and inter-day precisions were less than 9.36% in all cases. After strict validation, the method indicated good performance in terms of reproducibility, specificity, linearity, precision and accuracy, and it was successfully applied to the pharmacokinetic study of Garenoxacin in rats after oral administration.

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Metabolism and Disposition of Novel Des-Fluoro Quinolone Garenoxacin in Experimental Animals and an Interspecies Scaling of Pharmacokinetic Parameters

Cited by 33 publications

References 21 publications

Unusual Glucuronides

Unusual Glucuronides

Identification of a NovelN-Carbamoyl Glucuronide: In Vitro, In Vivo, and Mechanistic Studies

Solid Phase Extraction-HPLC Method for Determination and Pharmacokinetic Study of Garenoxacin in Rat Plasma after Oral Administration

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