Peringatan Keamanan

Topiroxostat is not reported to be carcinogenic, genotoxic, or teratogenic L867. Some reported adverse events of topiroxostat therapy include nasopharyngitis, pain in extremity, elevated alanine aminotransferase (ALT), decreased white blood cell count, eczema and gout arthritis. The no-observed-adverse-effect-level (NOAEL) was determined to be ?300 mg/kg/day in a study of once-daily, 52-week oral administration of 0/10/30/100 mg/kg/day topiroxostat in monkeys L867.

Topiroxostat

DB01685

small molecule experimental

Deskripsi

Topiroxostat is a selective xanthine oxidase inhibitor developed for treatment and management of hyperuricemia and gout. Xanthine oxidase, or xanthine oxidoreductase (XOR), regulates purine metabolism, and inhibition of the enzyme results in efficacious reduction of serum urate levels. Xanthine oxidase inhibitors are classified into two groups; purine analogs such as DB00437 and DB05262, and non-purine agents which includes topiroxostat. While DB00437 is considered a first-line therapy in treating hyperuricemic conditions, it is often associated with side effects and ineffective in reducing uric acid levels under recommended dosing regimens. Renal complications are major comorbidities that limit the DB00437 therapy as dose reductions are recommended. Topiroxostat and its metabolites are shown to be unaffected by renal complications, thus may be effective in patients with chronic kidney diseases A19657. Approved for therapeutic use in Japan since 2013, topiroxostat is marketed under the name Topiloric and Uriadec and is orally administered twice daily.

Struktur Molekul 2D

Berat 248.2428
Wujud solid

Peta Jejaring Molekuler
Legenda: Obat • Target • Gen • Enzim • (Panah → menunjukkan arah efek / relasi) • Transporter • Carrier

Profil Farmakokinetik

Waktu Paruh (Half-Life) The mean half life of topiroxostat after a single oral dose of 20mg topiroxostat is 5 hours under fasting condition. The complex of molybdenum (IV)- topiroxostat has an approximate half life of 20.4 hours [L867].
Volume Distribusi The mean ± SD apparent volume of distribution under fasted conditions is 1212.4 ± 1094.5 L. Under fed conditions, it is 704.6 ± 308.4 L. The distribution of 14C-topiroxostat (20, 200, and 2000 ng/mL) in human blood cells was 6.7% to 12.8% [L867].
Klirens (Clearance) The apparent total body clearance rate is 89.5 L/h and the renal clearance rate is 17.4 mL/h following a single oral dose of 20mg topiroxostat [L867].

Absorpsi

The time to reach peak plasma concentration of 229.9 ng/mL was 0.67 hour following a single oral dose of 20mg topiroxostat L867. The oral bioavailability in male rats was 69.6% after oral administration of a single dose of 1mg/kg L867.

Metabolisme

Topiroxostat is mainly inactivated by hepatic metabolism. 2-hydroxy topiroxostat is formed from primary hydroxylation of the drug by xanthine oxidase and still retains an inhibitory activity on the enzyme A19656. Topiroxostat N-oxide is another major metabolite that can be detected in plasma and urine. It is determined that the N-oxide and hydroxide metabolites are pyridine N-oxide and pyridine 2 (or 6)-hydroxide, respectively A19664. Topiroxostat is mainly inactivated by hepatic metabolism where it undergoes glucuronidation. The metabolism of topiroxostat to N1-and N2-glucuronide conjugates is mainly mediated by UGT1A1, 1A7, and 1A9, with UGT1A9 being the most predominant L867.

Rute Eliminasi

Urinary excretion and fecal excretion of radiolabeled topiroxostat are 30.4% and 40.9% of total dose of 1mg/kg administered to rats, respectively. Within 24 h after a single oral administration of 120mg of topiroxostat, the main metabolites of topiroxostat, N-oxide, N1-gluculonide, and N2-gluculonide, are excreted into urine about 4.8, 43.3, and 16.1 % of the dose, respectively. Unchanged topiroxostat and the hydroxide metabolite was 0.1% or less A19664.

Interaksi Obat

1129 Data
Cilostazol The serum concentration of Cilostazol can be increased when it is combined with Topiroxostat.
Eliglustat The metabolism of Eliglustat can be decreased when combined with Topiroxostat.
Ibrutinib The metabolism of Ibrutinib can be decreased when combined with Topiroxostat.
Colchicine The metabolism of Colchicine can be decreased when combined with Topiroxostat.
Fentanyl Fentanyl may decrease the excretion rate of Topiroxostat which could result in a higher serum level.
Iloperidone The metabolism of Iloperidone can be decreased when combined with Topiroxostat.
Retapamulin The metabolism of Retapamulin can be decreased when combined with Topiroxostat.
Tofacitinib The metabolism of Tofacitinib can be decreased when combined with Topiroxostat.
Vardenafil The metabolism of Vardenafil can be decreased when combined with Topiroxostat.
Eszopiclone The metabolism of Eszopiclone can be decreased when combined with Topiroxostat.
Zopiclone The metabolism of Zopiclone can be decreased when combined with Topiroxostat.
Lovastatin The metabolism of Lovastatin can be decreased when combined with Topiroxostat.
Alfuzosin The metabolism of Alfuzosin can be decreased when combined with Topiroxostat.
Alprazolam The metabolism of Alprazolam can be decreased when combined with Topiroxostat.
Succinic acid The excretion of Succinic acid can be decreased when combined with Topiroxostat.
Citrulline The excretion of Citrulline can be decreased when combined with Topiroxostat.
Aminohippuric acid The excretion of Aminohippuric acid can be decreased when combined with Topiroxostat.
Cefdinir The excretion of Cefdinir can be decreased when combined with Topiroxostat.
Leucovorin The excretion of Leucovorin can be decreased when combined with Topiroxostat.
Fluorescein The excretion of Fluorescein can be decreased when combined with Topiroxostat.
Hydrocortisone The excretion of Hydrocortisone can be decreased when combined with Topiroxostat.
Tetracycline The excretion of Tetracycline can be decreased when combined with Topiroxostat.
Ranitidine The excretion of Ranitidine can be decreased when combined with Topiroxostat.
Quinapril The excretion of Quinapril can be decreased when combined with Topiroxostat.
Dinoprostone The excretion of Dinoprostone can be decreased when combined with Topiroxostat.
Famotidine The excretion of Famotidine can be decreased when combined with Topiroxostat.
Fexofenadine The excretion of Fexofenadine can be decreased when combined with Topiroxostat.
Benzylpenicillin The excretion of Benzylpenicillin can be decreased when combined with Topiroxostat.
Captopril The excretion of Captopril can be decreased when combined with Topiroxostat.
Tazobactam The excretion of Tazobactam can be decreased when combined with Topiroxostat.
Cyclic adenosine monophosphate The excretion of Cyclic adenosine monophosphate can be decreased when combined with Topiroxostat.
Cholic Acid The excretion of Cholic Acid can be decreased when combined with Topiroxostat.
Glutaric Acid The excretion of Glutaric Acid can be decreased when combined with Topiroxostat.
Oxalic Acid The excretion of Oxalic Acid can be decreased when combined with Topiroxostat.
Taurocholic acid The excretion of Taurocholic acid can be decreased when combined with Topiroxostat.
Saxagliptin The excretion of Saxagliptin can be decreased when combined with Topiroxostat.
Ellagic acid The excretion of Ellagic acid can be decreased when combined with Topiroxostat.
Avibactam The excretion of Avibactam can be decreased when combined with Topiroxostat.
Eluxadoline The excretion of Eluxadoline can be decreased when combined with Topiroxostat.
Silibinin The excretion of Silibinin can be decreased when combined with Topiroxostat.
Relebactam The excretion of Relebactam can be decreased when combined with Topiroxostat.
Cefotiam The excretion of Cefotiam can be decreased when combined with Topiroxostat.
Tenofovir disoproxil The excretion of Tenofovir disoproxil can be decreased when combined with Topiroxostat.
Indomethacin The excretion of Indomethacin can be decreased when combined with Topiroxostat.
Cephalexin The excretion of Cephalexin can be decreased when combined with Topiroxostat.
Valaciclovir The excretion of Valaciclovir can be decreased when combined with Topiroxostat.
Acyclovir The excretion of Acyclovir can be decreased when combined with Topiroxostat.
Cefaclor The excretion of Cefaclor can be decreased when combined with Topiroxostat.
Hydrochlorothiazide The excretion of Hydrochlorothiazide can be decreased when combined with Topiroxostat.
Cefazolin The excretion of Cefazolin can be decreased when combined with Topiroxostat.
Ceftizoxime The excretion of Ceftizoxime can be decreased when combined with Topiroxostat.
Cefacetrile The excretion of Cefacetrile can be decreased when combined with Topiroxostat.
Ceftibuten The excretion of Ceftibuten can be decreased when combined with Topiroxostat.
Cefaloridine The excretion of Cefaloridine can be decreased when combined with Topiroxostat.
Tenofovir alafenamide The serum concentration of Tenofovir alafenamide can be increased when it is combined with Topiroxostat.
Tenofovir The excretion of Tenofovir can be decreased when combined with Topiroxostat.
Oseltamivir The excretion of Oseltamivir can be decreased when combined with Topiroxostat.
Piperacillin The excretion of Piperacillin can be decreased when combined with Topiroxostat.
Trifluridine The excretion of Trifluridine can be decreased when combined with Topiroxostat.
Cimetidine The excretion of Cimetidine can be decreased when combined with Topiroxostat.
Levocarnitine The excretion of Levocarnitine can be decreased when combined with Topiroxostat.
Doripenem The excretion of Doripenem can be decreased when combined with Topiroxostat.
Dexamethasone The excretion of Dexamethasone can be decreased when combined with Topiroxostat.
Oxytetracycline The excretion of Oxytetracycline can be decreased when combined with Topiroxostat.
Prednisolone phosphate The excretion of Prednisolone phosphate can be decreased when combined with Topiroxostat.
Dexamethasone acetate The excretion of Dexamethasone acetate can be decreased when combined with Topiroxostat.
Acamprosate The excretion of Acamprosate can be decreased when combined with Topiroxostat.
Warfarin The serum concentration of Warfarin can be increased when it is combined with Topiroxostat.
Acenocoumarol The serum concentration of Acenocoumarol can be increased when it is combined with Topiroxostat.
(R)-warfarin The serum concentration of (R)-warfarin can be increased when it is combined with Topiroxostat.
R,S-Warfarin alcohol The serum concentration of R,S-Warfarin alcohol can be increased when it is combined with Topiroxostat.
S,R-Warfarin alcohol The serum concentration of S,R-Warfarin alcohol can be increased when it is combined with Topiroxostat.
(S)-Warfarin The serum concentration of (S)-Warfarin can be increased when it is combined with Topiroxostat.
Midazolam The serum concentration of Midazolam can be increased when it is combined with Topiroxostat.
Tacrolimus The serum concentration of Tacrolimus can be increased when it is combined with Topiroxostat.
Atorvastatin The metabolism of Atorvastatin can be decreased when combined with Topiroxostat.
Troglitazone The metabolism of Troglitazone can be decreased when combined with Topiroxostat.
Torasemide The metabolism of Torasemide can be decreased when combined with Topiroxostat.
Dapsone The metabolism of Dapsone can be decreased when combined with Topiroxostat.
Diethylstilbestrol The metabolism of Diethylstilbestrol can be decreased when combined with Topiroxostat.
Morphine The metabolism of Morphine can be decreased when combined with Topiroxostat.
Omeprazole The metabolism of Omeprazole can be decreased when combined with Topiroxostat.
Diltiazem The metabolism of Diltiazem can be decreased when combined with Topiroxostat.
Trimethadione The metabolism of Trimethadione can be decreased when combined with Topiroxostat.
Sulfadiazine The metabolism of Sulfadiazine can be decreased when combined with Topiroxostat.
Rosiglitazone The metabolism of Rosiglitazone can be decreased when combined with Topiroxostat.
Lansoprazole The metabolism of Lansoprazole can be decreased when combined with Topiroxostat.
Quinine The metabolism of Quinine can be decreased when combined with Topiroxostat.
Mephenytoin The metabolism of Mephenytoin can be decreased when combined with Topiroxostat.
Piroxicam The metabolism of Piroxicam can be decreased when combined with Topiroxostat.
Diclofenac The metabolism of Diclofenac can be decreased when combined with Topiroxostat.
Chloroquine The metabolism of Chloroquine can be decreased when combined with Topiroxostat.
Amodiaquine The metabolism of Amodiaquine can be decreased when combined with Topiroxostat.
Paramethadione The metabolism of Paramethadione can be decreased when combined with Topiroxostat.
Nicardipine The metabolism of Nicardipine can be decreased when combined with Topiroxostat.
Verapamil Verapamil may decrease the excretion rate of Topiroxostat which could result in a higher serum level.
Estradiol The excretion of Estradiol can be decreased when combined with Topiroxostat.
Naproxen The metabolism of Naproxen can be decreased when combined with Topiroxostat.
Tazarotene The metabolism of Tazarotene can be decreased when combined with Topiroxostat.
Propofol The metabolism of Propofol can be decreased when combined with Topiroxostat.

Target Protein

Xanthine dehydrogenase/oxidase XDH

Referensi & Sumber

Artikel (PubMed)
  • PMID: 20952484
    Matsumoto K, Okamoto K, Ashizawa N, Nishino T: FYX-051: a novel and potent hybrid-type inhibitor of xanthine oxidoreductase. J Pharmacol Exp Ther. 2011 Jan;336(1):95-103. doi: 10.1124/jpet.110.174540. Epub 2010 Oct 15.
  • PMID: 24448692
    Hosoya T, Ohno I, Nomura S, Hisatome I, Uchida S, Fujimori S, Yamamoto T, Hara S: Effects of topiroxostat on the serum urate levels and urinary albumin excretion in hyperuricemic stage 3 chronic kidney disease patients with or without gout. Clin Exp Nephrol. 2014 Dec;18(6):876-84. doi: 10.1007/s10157-014-0935-8. Epub 2014 Jan 22.
  • PMID: 25501928
    Nishino T, Okamoto K: Mechanistic insights into xanthine oxidoreductase from development studies of candidate drugs to treat hyperuricemia and gout. J Biol Inorg Chem. 2015 Mar;20(2):195-207. doi: 10.1007/s00775-014-1210-x. Epub 2014 Dec 12.
  • PMID: 24214189
    Sugiyama A, Hashimoto H, Nakamura Y, Fujita T, Kumagai Y: QT/QTc study conducted in Japanese adult healthy subjects: a novel xanthine oxidase inhibitor topiroxostat was not associated with QT prolongation. J Clin Pharmacol. 2014 Apr;54(4):446-52. doi: 10.1002/jcph.226. Epub 2013 Nov 22.
  • PMID: 12421831
    Okamoto K, Eger BT, Nishino T, Kondo S, Pai EF, Nishino T: An extremely potent inhibitor of xanthine oxidoreductase. Crystal structure of the enzyme-inhibitor complex and mechanism of inhibition. J Biol Chem. 2003 Jan 17;278(3):1848-55. Epub 2002 Nov 5.
  • PMID: 15148401
    Okamoto K, Matsumoto K, Hille R, Eger BT, Pai EF, Nishino T: The crystal structure of xanthine oxidoreductase during catalysis: implications for reaction mechanism and enzyme inhibition. Proc Natl Acad Sci U S A. 2004 May 25;101(21):7931-6. Epub 2004 May 17.
  • PMID: 16914512
    Nakazawa T, Miyata K, Omura K, Iwanaga T, Nagata O: Metabolic profile of FYX-051 (4-(5-pyridin-4-yl-1h-1,2,4triazol-3-yl)pyridine-2-carbonitrile) in the rat, dog, monkey, and human: identification of N-glucuronides and N-glucosides. Drug Metab Dispos. 2006 Nov;34(11):1880-6. Epub 2006 Aug 16.
  • PMID: 17761779
    Omura K, Nakazawa T, Sato T, Iwanaga T, Nagata O: Characterization of N-glucuronidation of 4-(5-pyridin-4-yl-1H-1,2,4triazol-3-yl) pyridine-2-carbonitrile (FYX-051): a new xanthine oxidoreductase inhibitor. Drug Metab Dispos. 2007 Dec;35(12):2143-8. Epub 2007 Aug 30.
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Contoh Produk & Brand

Produk: 0 • International brands: 2
International Brands
  • Topiloric — Fujiyakuhin Co.
  • Uriadec — Sanwa Kagaku Kenkyusho Co.

Sekuens Gen/Protein (FASTA)

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