Metabolism of S-1108, a new oral cephem antibiotic, and metabolic profiles of its metabolites in humans

Totsuka, Kyoichi; Shimizu, Kihachiro; Konishi, Masaharu; Yamamoto, Sadaki

doi:10.1128/aac.36.4.757

Cited by 35 publications

(30 citation statements)

References 16 publications

(25 reference statements)

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“…This increase of Tol-Car is in accordance with the reported induction of carnitine acyl transferases (Katsutani et al, 2000) and increases in free carnitine and CoA levels after pretreatment with fibrates (Gregus et al, 1998). Acyl carnitine esters are rarely observed metabolites of xenobiotic carboxylic acids, and to our knowledge, the only xenobiotic carnitine esters that have been previously identified in vivo are the pivaloyl (Vickers et al, 1985;Totsuka et al, 1992), valproyl (Melegh et al, 1990), and zomepirac carnitine esters (Olsen et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Studies on the Metabolism of Tolmetin to the Chemically Reactive Acyl-Coenzyme A Thioester Intermediate in Rats

Olsen

Li²,

Skonberg³

et al. 2007

Drug Metab Dispos

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ABSTRACT:Carboxylic acids may be metabolized to acyl glucuronides and acyl-coenzyme A thioesters (acyl-CoAs), which are reactive metabolites capable of reacting with proteins in vivo. In this study, the metabolic activation of tolmetin (Tol) to reactive metabolites and the subsequent formation of Tol-protein adducts in the liver were studied in rats. Two hours after dose administration (100 mg/kg i.p.), tolmetin acyl-CoA (Tol-CoA) was identified by liquid chromatography-tandem mass spectrometry in liver homogenates. Similarly, the acyl-CoA-dependent metabolites tolmetin-taurine conjugate (Tol-Tau) and tolmetin-acyl carnitine ester (Tol-Car) were identified in rat livers. In a rat bile study (100 mg/kg i.p.), the S-acyl glutathione thioester conjugate was identified, providing further evidence of the formation of reactive metabolites such as Tol-CoA or Tol-acyl glucuronide (Tol-O-G), capable of acylating nucleophilic functional groups. Three rats were treated with clofibric acid (150 mg/kg/day i.p. for 7 days) before dose administration of Tol. This resulted in an increase in covalent binding to liver proteins from 0.9 nmol/g liver in control rats to 4.2 nmol/g liver in clofibric acidtreated rats. Similarly, levels of Tol-CoA increased from 0.6 nmol/g to 4.4 nmol/g liver after pretreatment with clofibric acid, whereas the formation of Tol-O-G and Tol-Tau was unaffected by clofibric acid treatment. However, Tol-Car levels increased from 0.08 to 0.64 nmol/g after clofibric acid treatment. Collectively, these results confirm that Tol-CoA is formed in vivo in the rat and that this metabolite can have important consequences in terms of covalent binding to liver proteins.Drugs with a carboxylate functional group can be metabolized to chemically reactive metabolites that react with nucleophilic amino acids of proteins to form drug-protein adducts (Boelsterli, 2002;Bailey and Dickinson, 2003). Tolmetin (Tol; 5-[4Ј-methylbenzoyl]-1-methylpyrrole-2-acetic acid) is an example of a carboxylic acidcontaining drug which, in humans, is partly metabolized to the acyl glucuronide (Hyneck et al., 1987). In vitro studies have shown that the tolmetin-acyl glucuronide (Tol-O-G) is a reactive metabolite that reacts with the amino acid side chains of lysine, arginine, and serine present in human serum albumin (Ding et al., 1993(Ding et al., , 1995.Covalent binding of Tol has also been studied in humans, where Tol-protein adducts have been detected in plasma (Hyneck et al., 1988;Zia-Amirhosseini et al., 1994). Tol-protein adducts in plasma were believed to result from reaction of the acyl glucuronide with plasma proteins, since a good correlation between covalent plasmaprotein adducts and exposure to Tol-O-G was observed (Hyneck et al., 1988). In the liver, other metabolic pathways may contribute to Tol-protein adduct formation. In a recent study, it has been shown that the pyrrole moiety of Tol may undergo bioactivation to a reactive arene oxide (Chen et al., 2006). Other reports have shown that acyl-coenzyme A thioesters (acyl-CoAs) a...

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Section: Discussionmentioning

confidence: 99%

Studies on the Metabolism of Tolmetin to the Chemically Reactive Acyl-Coenzyme A Thioester Intermediate in Rats

Olsen

Li²,

Skonberg³

et al. 2007

Drug Metab Dispos

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“…Furthermore, it is suggested that a side effect such as muscle disorders may be unlikely in humans because the pivalic acid left from S-1108 is almost quantitatively conjugated with carnitine in the human body and is excreted rapidly into the urine (21,28). The safety of the clinical use of S-1108 given at 200 mg three times a day has been established in phase I clinical studies (21,27).…”

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confidence: 99%

“…Free pivalic acid accounted for most of the radioactivity in plasma following the administration of [pivaloyl- 14 C]S-1108 in both rats and rabbits. There is a great difference in the metabolic profile of pivalic acid between animals and humans; free pivalic acid was hardly found in human plasma (28).…”

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confidence: 99%

Disposition of S-1108, a new oral cephem antibiotic, and metabolic fate of pivalic acid liberated from [pivaloyl-14C]S-1108 in rats and dogs

Mizojiri

Futaguchi

Norikura

et al. 1995

Antimicrob Agents Chemother

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[pivaloyl-14 C]S-1108, which is 14 C labeled at the pivalic acid moiety of the pivaloyloxymethyl side chain of S-1108, was administered orally to rats and dogs, and the disposition of pivalic acid cleft from S-1108 was examined. Besides pivaloylcarnitine and pivaloylglucuronide, pivaloylglycine was identified in dog urine as a metabolite of pivalic acid by thin-layer chromatography and high-performance liquid chromatography analysis. The concentrations in the plasma of rats to which doses of 6.65, 26.6, and 532 mg/kg of body weight were administered showed dose-proportionate levels. The radioactivity was eliminated rapidly, with a half-life of approximately 3 h until 24 h at both the 6.65-and 26.6-mg/kg doses. Free pivalic acid in plasma accounted for more than 80% of the concentration of radioactivity. Radioactivity was distributed throughout the body and was eliminated quickly at a rate similar to that of radioactivity from plasma. Most of the absorbed radioactivity was excreted in the urine, and it was completed within 24 h after administration. In dogs, the half-life of radioactivity in plasma was longer than that in the rats. The ratio of free pivalic acid in plasma was 60 to 70% of the radioactivity in plasma. The concentration of radioactivity in the liver, cortex of the kidney, and skeletal muscle 144 h after oral dosing was more than 10 times higher than the concentration in plasma for all doses. Urinary excretion in dogs was slower than that in rats. The differences in the disposition of pivalic acid between dogs and rats may account for differences in the degree of skeletal muscle disorders. The safety in humans of S-1108 given at 200 mg three times a day is discussed in relation to the metabolic formation of the carnitine conjugate of pivalic acid and the reduction of the carnitine concentration in plasma.S-1108 is a new oral cephem antibiotic and is a prodrug of S-1006 (12); the absorbability of S-1006 increases by esterification of the carboxy group at the C-4 position of the cephem ring with pivaloyloxymethyl (POM). S-1108 is hydrolyzed to the active moiety, S-1006, and components of the ester residue, formaldehyde and pivalic acid, by an esterase in the gut wall.

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“…It was reported that the generated formaldehyde was rapidly metabolized and the produced carbon dioxide was excreted via expiration, as in the pivoxil series. [29][30][31][32] The hydrolysates were analyzed by HPLC, as shown in Fig. 3.…”

Section: Resultsmentioning

confidence: 99%

Prodrug Study of Plinabulin Using a Click Strategy Focused on the Effects of a Replaceable Water-Solubilizing Moiety

Yakushiji

Tanaka

Muguruma

et al. 2012

CHEMICAL & PHARMACEUTICAL BULLETIN

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Plinabulin (1) is a potent anti-microtubule agent, however, its low water solubility has to be improved for the advantage in pharmacokinetics and chemotherapy. In this report, the replaceable water-solubilizing moiety of the water-soluble prodrug of plinabulin (1) was investigated. The properties of the water-soluble prodrugs of plinabulin (1), in which the water-solubilizing part was replaced with a new functionality, were evaluated. The newly introduced water-solubilizing moiety provided interesting effects on the water solubility and half-life of the prodrugs.Key words water-soluble prodrug; anti-microtubule agent; click chemistry; plinabulin; monolactim 'Prodrug' research is one of the most important fields of medicinal chemistry. In particular, improvements in water solubility have been studied extensively.1) Paclitaxel, for example, exhibited potent anti-microtubule activity 2) as intravenous (i.v.) injection. Due to its low water solubility (0.25 µg/mL), 3) it was initially formulated with the detergent cremophor EL, which induced hypersensitivity. 4) Therefore, a variety of water-soluble paclitaxel prodrugs have been developed to improve the patient's burden. 5-9)Previously, we reported the design and synthesis of a water-soluble prodrug of plinabulin (1) 10) as a monolactim serine-type derivative 2 11) using click chemistry 12-14) (Fig. 1). Plinabulin (NPI-2358) (1) (cytotoxic activity: IC 50 =15 nM in HT-29 cells) is a derivative of S-(−)-phenylahistin 15,16) and phase II clinical trials have been undertaken worldwide [17][18][19] by way of i.v. injection as a promising vascular disrupting agent (VDA). [20][21][22][23][24] Plinabulin (1) showed low water solubility (<0.1 µg/mL), which forced the co-injection of a solubilizing agent, such as paclitaxel. To improve the pharmacokinetics and chemotherapeutic index, the water-soluble prodrug 2 was developed. The water solubility of α-amino acid type derivative 2 was determined to be 6.38 mg/mL, and the in vitro halflife (t 1/2 ) in the presence of porcine liver esterase was found to be 59.9 min. These values make the compound appropriate for i.v. injection without inclusion of a solubilizing agent. Furthermore, the water-solubilizing triazole auxiliary, which was cleaved from the mother skeleton via an esterase hydrolysis reaction, was shown to be cellularly non-toxic.11) These results suggested that it was worthwhile to pursue further optimization of this prodrug system.In this paper, we investigated the replaceable water-solubilizing moiety to evaluate its influence on prodrug water solubility and half-life. As a water-solubilizing moiety, we focused on two types of polar groups. One was L-carnitine (3), 25) which is an γ-amino acid derivative involved in lipid metabolism in the human body. The unprotected polar functional group of the azide 4 26) is a β-hydroxycarboxylic acid moiety, that is similar to the serine-type structure used in prodrug 2, with a higher number of carbon atoms. These slight changes were expected to provide interesting effects on th...

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Metabolism of S-1108, a new oral cephem antibiotic, and metabolic profiles of its metabolites in humans

Cited by 35 publications

References 16 publications

Studies on the Metabolism of Tolmetin to the Chemically Reactive Acyl-Coenzyme A Thioester Intermediate in Rats

Studies on the Metabolism of Tolmetin to the Chemically Reactive Acyl-Coenzyme A Thioester Intermediate in Rats

Disposition of S-1108, a new oral cephem antibiotic, and metabolic fate of pivalic acid liberated from [pivaloyl-14C]S-1108 in rats and dogs

Prodrug Study of Plinabulin Using a Click Strategy Focused on the Effects of a Replaceable Water-Solubilizing Moiety

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