<b><i>In vitro</i></b>drug–drug interaction studies with febuxostat, a novel non-purine selective inhibitor of xanthine oxidase: plasma protein binding, identification of metabolic enzymes and cytochrome P450 inhibition

Mukoyoshi, M; Nishimura, Shinichi; Hoshide, S.; Umeda, Sachiko; Kanou, Masanobu; Taniguchi, Kaoru; Muroga, H

doi:10.1080/00498250801956350

Cited by 56 publications

(43 citation statements)

References 23 publications

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“…Метаболизируется фебуксостат преимущественно в печени за счет связи с глюкуронозилтрансферазой [46]. Примерно 25-45% препарата экскретируется с мочой в конъюгированном виде, и только 1-6% выводится в неиз-мененном виде [38,41,42,44].…”

Section: фармакокинетические свойстваunclassified

“…Изучение влияния фебуксостата на ферменты цитохрома Р450 (CYP) свиде-тельствует о том, что препарат не оказывает значимого влияния на активность ферментных систем CYP [46]. Взаимодействие с диуретиками до настоящего време-ни широко не изучалось, однако назначение одновре-менно 80 мг фебуксостата и 50 мг гидрохлортиазида в сутки в течение 7 дней не влияло на фармакокинетику фебуксостата, хотя и приводило к недостоверному повы-шению сывороточного уровня МК [47].…”

Section: лекарственные взаимодействияunclassified

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Febuxostat for Treatment of Chronic Hyperuricemia in Gout Patients

Петрова¹,

Мазуров²,

Инамова³

2017

Med. sov.

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ВВЕДЕНИЕПодагра -заболевание, которое связано с отложением кристаллов мочевой кислоты в суставах и околосуставных тканях, клиническими проявлениями его являются приступы острого артрита, рецидивирующие артриты, упорное хрони-ческое воспаление низких градаций, формирование тофу-сов, а также кристаллизация солей мочевой кислоты в интер-стициальной ткани почек. Подагра является достаточно частой причиной воспалительных артритов у мужчин [1, 2], хотя нередко она встречается и у женщин в постменопау-зальном периоде [3]. Общий показатель распространенно-сти в мире составляет 0,08% [4]. По сравнению с предыду-щими десятилетиями ее частота увеличилась [5,8]. Так, например, в США она составляет 3,9% [6], в Великобритании -2,49% [7,9]. В возрасте 75 лет и старше подагра выявляется у 7% мужчин [10], среди населения Новой Зеландии в той же возрастной группе этот показатель достигает 30% [11]. К причинам увеличения частоты гиперурикемии среди насе-ления разных стран мира относятся увеличение потребле-ния продуктов, богатых пуринами, безалкогольных напитков с фруктозой, а также увеличение потребления алкоголя [12]. Кроме того, глобальное распространение ожирения также способствует «эпидемии» гиперурикемии [6,7,9] Следует отметить, что подагра связана со значитель-ными экономическими затратами [13,14]. Так, длитель-ность временной нетрудоспособности у пациентов с подагрой моложе 65 лет составляет 25,1 дня в год, а эпизоды острой подагры приводят к потере в среднем 17,1 дня трудоспособности в год [15]. Febuxostat, a selective inhibitor of isoforms xantinoxydoreductase, it is an alternative to a limited number of medications to reduce urates levels applied in recent decades. Inhibition of xantinoxydoreductase by febuxostat more is more powder and effective than by allopurinol, as evidenced by more frequent achievement of target urate level in the blood serum, especially in patients with high urates concentration. Unlike allopurinol pharmacokinetic properties febuxostat do not depend to a large extent on renal clearance, which is important for patients with chronic renal disease. A few studies conducted further evaluation of the febuxostat safety for the cardiovascular system and its potential positive impact on renal function. It is also important that elderly patients didn't require correction doses of the drug.

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Section: фармакокинетические свойстваunclassified

Section: лекарственные взаимодействияunclassified

Febuxostat for Treatment of Chronic Hyperuricemia in Gout Patients

Петрова¹,

Мазуров²,

Инамова³

2017

Med. sov.

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Section: Drug Interactionsmentioning

confidence: 99%

“…In vitro studies showed the presence of ibuprofen or warfarin did not change the plasma protein binding of febuxostat and febuxostat did not infl uence the plasma protein binding of ibuprofen or warfarin, suggesting that febuxostat was unlikely to cause a drug-drug interaction by displacement of protein binding (Mukoyoshi et al 2008). Examination of the inhibitory effect of febuxostat on CYP enzymes suggested that it had minimal inhibitory effect on the activities of any CYP (Mukoyoshi et al 2008). Based on the in vitro study that showed febuxostat had a weak inhibitory effect on CYP2D6, but no effect on CYP1A2, CYP2C9, CYP2C19 or CYP3A4, Khosravan et al (2005b) examined the effect of multiple doses of febuxostat 120 mg daily on the pharmacokinetics of desipramine, a substrate for CYP2D6.…”

Section: Drug Interactionsmentioning

confidence: 99%

Febuxostat in the management of hyperuricemia and chronic gout: a review

Tomlinson

2008

TCRM

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Abstract:Febuxostat is a novel, potent, non-purine selective xanthine oxidase inhibitor, which in clinical trials demonstrated superior ability to lower and maintain serum urate levels below 6 mg/dL compared with conventionally used doses of allopurinol. Febuxostat was well tolerated in long term treatment in patients with hyperuricemia including those experiencing hypersensitity/intolerance to allopurinol. Dose adjustment appears unnecessary in patients with mild to moderate renal or liver insuffi ciency or advanced age. The most common adverse reactions reported were abnormal liver function tests, headache, and gastrointestinal symptoms, which were usually mild and transient. However, whether hepatotoxicity becomes a limitation in the use of febuxostat needs to be determined in further studies. An increased frequency of gout fl ares occurs for a prolonged period after treatment initiation, as with any aggressive lowering of serum urate, and prolonged prophylaxis with colchicine or NSAIDs is usually required. Febuxostat has been granted marketing authorization by the European Commission in early 2008 for the treatment of chronic hyperuricemia and gout. Febuxostat is the fi rst major treatment alternative for gout in more than 40 years and is a promising alternative to allopurinol, although continued long-term surveillance on safety and effi cacy is required.

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“…5) Therefore, it is necessary for patients with renal impairment to receive a reduced dose. 6) On the other hand, as febuxostat, a once-a-day non-purine xanthine oxidase inhibitor, is excreted into feces and urine in a well-balanced manner after being metabolized in the liver, 7,8) febuxostat can be safely used in patients with mild, moderate or severe renal impairment. 9,10) Therefore, there are many cases of switching from allopurinol to febuxostat in patients who have allopurinol resistance or in whom allopurinol is difficult to use due to renal impairment.…”

mentioning

confidence: 99%

Previous Dosage of Allopurinol Is a Strong Determinant of Febuxostat Efficacy

Koide

Hira

Tsujimoto

et al. 2017

Biological & Pharmaceutical Bulletin

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Febuxostat has currently played pivotal role in the treatment of hyperuricemia, but there is little comprehensive information for the determinants of individual difference in efficacy of febuxostat. Therefore, the present study, a retrospective investigation, was carried out to analyze the effects of patient characteristics on the efficacy of febuxostat. A total of 225 patients who were continuously prescribed the same dose of febuxostat for 8-12 weeks from the initial therapy were enrolled in the present study. The data, including patient information and laboratory data, were collected from electronic medical records. Serum urate lowering effects of febuxostat were evaluated by calculating the change in serum urate level at baseline and at 8-12 weeks after starting febuxostat. The multiple regression analysis showed the change in serum urate level was significantly lower in male patients and in those with a lower baseline serum urate level, higher previous dose of allopurinol, lower dose of febuxostat and lower body surface area-unadjusted estimated glomerular filtration rate. Concomitantly administered drugs did not show a significantly influence on the efficacy of febuxostat. In conclusion, it should be noted that the serum urate lowering efficacy of febuxostat may decrease in patients with a higher previous dose of allopurinol, renal impairment or male patients. The basic findings of the present study are believed to contribute to the proper use of febuxostat.

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In vitrodrug–drug interaction studies with febuxostat, a novel non-purine selective inhibitor of xanthine oxidase: plasma protein binding, identification of metabolic enzymes and cytochrome P450 inhibition

Cited by 56 publications

References 23 publications

Febuxostat for Treatment of Chronic Hyperuricemia in Gout Patients

Febuxostat for Treatment of Chronic Hyperuricemia in Gout Patients

Febuxostat in the management of hyperuricemia and chronic gout: a review

Previous Dosage of Allopurinol Is a Strong Determinant of Febuxostat Efficacy

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