Comparative Metabolism of<sup>14</sup>C-Labeled Apixaban in Mice, Rats, Rabbits, Dogs, and Humans

Zhang, Donglu; He, Kan; Raghavan, Nirmala; Wang, Lifei; Mitroka, James; Maxwell, Brad D.; Knabb, Robert M.; Frost, Charles A; Schuster, Alan; Feng, Hao; Gu, Zhe‐Ming; Humphreys, W. Griffith; Grossman, Scott J.

doi:10.1124/dmd.108.025981

Cited by 101 publications

(83 citation statements)

References 30 publications

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“…Apixaban was metabolized by numerous pathways and enzymes, primarily CYP3A4/5, with relatively minor contributions by CYP1A2, 2J2, 2C8, 2C9, and 2C19. This multiple-pathway metabolism of apixaban, in combination with the contribution of renal and biliary clearance as well as intestinal secretion to elimination (urinary, biliary, or intestinal clearance was more important than metabolic clearance) Zhang et al, 2009), indicates that alternative elimination routes are available, should the primary metabolic enzymes be inhibited. Therefore, although apixaban may be the victim of drug-drug interactions with drugs that modulate P450 enzymes, such interactions are not likely to be of any significant magnitude.…”

Section: Metabolic Drug-drug Interaction Potential Of Apixabanmentioning

confidence: 99%

In Vitro Assessment of Metabolic Drug-Drug Interaction Potential of Apixaban through Cytochrome P450 Phenotyping, Inhibition, and Induction Studies

Wang¹,

Zhang²,

Raghavan³

et al. 2009

Drug Metab Dispos

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231

167

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ABSTRACT:Apixaban is an oral, direct, and highly selective factor Xa inhibitor in late-stage clinical development for the prevention and treatment of thromboembolic diseases. The metabolic drug-drug interaction potential of apixaban was evaluated in vitro. The compound did not show cytochrome P450 inhibition (IC 50 values >20 M) in incubations of human liver microsomes with the probe substrates of CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4/5. Apixaban did not show any effect at concentrations up to 20 M on enzyme activities or mRNA levels of selected P450 enzymes (CYP1A2, 2B6, and 3A4/5) that are sensitive to induction in incubations with primary human hepatocytes. Apixaban showed a slow metabolic turnover in incubations of human liver microsomes with formation of O-demethylation (M2) and hydroxylation products (M4 and M7) as prominent in vitro metabolites. Experiments with human cDNA-expressed P450 enzymes and P450 chemical inhibitors and correlation with P450 activities in individual human liver microsomes demonstrated that the oxidative metabolism of apixaban for formation of all metabolites was predominantly catalyzed by CYP3A4/5 with a minor contribution of CYP1A2 and CYP2J2 for formation of M2. The contribution of CYP2C8, 2C9, and 2C19 to metabolism of apixaban was less significant. In addition, a human absorption, distribution, metabolism, and excretion study showed that more than half of the dose was excreted as unchanged parent (f m CYP <0.5), thus significantly reducing the overall metabolic drug-drug interaction potential of apixaban. Together with a low clinical efficacious concentration and multiple clearance pathways, these results demonstrate that the metabolic drug-drug interaction potential between apixaban and coadministered drugs is low.Apixaban (Fig. 1), a novel and highly selective inhibitor of factor Xa (Luettgen et al., 2006;Pinto et al., 2007;Wong et al., 2008), is under development for the treatment and prevention of thromboembolic disorders, prevention of stroke in patients with atrial fibrillation, and secondary prevention in patients with acute coronary syndromes (APPRAISE Steering Committee and Investigators, 2009). In addition to demonstrating high oral availability (Frost et al., 2007), clinical studies of apixiban have shown prevention of venous thromboembolic events in patients after knee replacement surgery (Lassen et al., 2007). Apixaban is efficacious and well tolerated in the treatment of patients with acute symptomatic deep vein thrombosis (Buller et al., 2008). After oral administration, apixaban was slowly metabolized and thus was mostly unchanged in the circulation although apixaban was metabolized by multiple pathways in animals and humans (Zhang et al., , 2010. The primary metabolic pathways of apixaban in humans included O-demethylation (M2) and hydroxylation (M4 and M7). M2 was further conjugated by sulfation to form a sulfate metabolite (M1) Wang et al., 2009). Other metabolites (M3, M5, and M6) previously identified as minor metabolites in animals and humans were als...

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Section: Metabolic Drug-drug Interaction Potential Of Apixabanmentioning

confidence: 99%

In Vitro Assessment of Metabolic Drug-Drug Interaction Potential of Apixaban through Cytochrome P450 Phenotyping, Inhibition, and Induction Studies

Wang¹,

Zhang²,

Raghavan³

et al. 2009

Drug Metab Dispos

Self Cite

231

167

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“…Metabolites in plasma, bile, and urine and fecal samples were profiled as described previously (Raghavan et al, 2009;Wang et al, 2011;Zhang et al, 2009a). Pooled plasma, urine, bile, or fecal homogenate samples were prepared by aliquoting appropriate volumes or weights of samples from each time interval.…”

Section: Materials Apixaban and [mentioning

confidence: 99%

“…Greater than 50% of radioactive dose was recovered in feces as the parent from rats, dogs, and humans following oral administration of [ 14 C]apixaban. Plasma radioactivity profiling has shown that apixaban represents .90% of all circulating drug-related components in rats and dogs and 75% in humans (Raghavan et al, 2009;Wang et al, 2011;Zhang et al, 2009a). Apixaban is metabolically stable in incubations with liver microsomes and hepatocytes and has a relatively low clearance with total plasma clearance of ,5% hepatic blood flow in rats, dogs, and humans Wong et al, 2011).…”

mentioning

confidence: 99%

“…1), 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4, 5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide, a highly selective, oral, direct inhibitor of Factor Xa, a protease enzyme that plays a pivotal role in the coagulation cascade, is a newly approved anticoagulant (Lassen et al, 2007;Connolly et al, 2011;Granger et al, 2011). Following oral administration of [ 14 C]apixaban in humans, both metabolism (25%) and urinary excretion (27%) were important clearance pathways (Raghavan et al, 2009;Zhang et al, 2009a). Greater than 50% of radioactive dose was recovered in feces as the parent from rats, dogs, and humans following oral administration of [ 14 C]apixaban.…”

mentioning

confidence: 99%

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Investigating the Enteroenteric Recirculation of Apixaban, a Factor Xa Inhibitor: Administration of Activated Charcoal to Bile Duct-Cannulated Rats and Dogs Receiving an Intravenous Dose and Use of Drug Transporter Knockout Rats

Zhang

Frost

et al. 2013

Drug Metab Dispos

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The study described here investigated the impact of intestinal excretion (IE; excretion of drug directly from circulation to intestinal lumen), enteroenteric recirculation (EER), and renal tubule recirculation (RTR) on apixaban pharmacokinetics and disposition. The experimental approaches involve integrating apixaban elimination pathways with pharmacokinetic profiles obtained from bile ductcannulated (BDC) rats and dogs receiving i.v. doses together with oral administration of activated charcoal (AC). Additionally, the role of P-gp (P-glycoprotein; abcb1) and BCRP (breast cancer resistance protein; abcg2) in apixaban disposition was evaluated in experiments using transporter inhibitors and transporter knockout (KO) rats. Approximately 20-50% of an apixaban i.v. dose was found in feces of BDC rats and dogs, suggesting IE leading to fecal elimination and intestinal clearance (IC). The fecal elimination, IC, and systemic clearance of apixaban were increased upon AC administration in both BDC rats and dogs and were decreased in BDC rats dosed with GF-120918, a dual BCRP and P-gp inhibitor). BCRP appeared to play a more important role for absorption and intestinal and renal elimination of apixaban than P-gp in transporter-KO rats after oral and i.v. dosing, which led to a higher level of active renal excretion in rat than other species. These data demonstrate that apixaban undergoes IE, EER, and RTR that are facilitated by efflux transporters. Intestinal reabsorption of apixaban could be interrupted by AC even at 3 hours post-drug dose in dogs (late charcoal effect). This study demonstrates that the intestine is an organ for direct clearance and redistribution of apixaban. The IE, EER, and RTR contribute to overall pharmacokinetic profiles of apixaban. IE as a clearance pathway, balanced with metabolism and renal excretion, helps decrease the impacts of intrinsic (renal or hepatic impairment) and extrinsic (drug-drug interactions) factors on apixaban disposition.

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“…Vartojant du kartus per parą, optimalus įsotinimas pasiekiamas per 3 paras [20]. Vaisto eliminacija vyksta per inkstus ir virškinimo traktą [21].…”

Section: Tyrimo Objektas Ir Metodasunclassified

TEG ir naujieji peroraliniai antikoaguliantai

et al. 2014

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Raktažodžiai: dabigatranas, rivaroksabanas, apiksabanas, tromboelastografija Santrauka Naujieji peroraliniai antikoaguliantai (NPA) -dabigatranas, rivaroksabanas, apiksabanas yra pranašes-ni už senuosius atstovus (vitamino K antagonistus ir mažos mokekulinės masės heparinus). NPA vartoti patogu ir saugu, tačiau sunkios traumos ar kitų kritinių būklių metu ūmaus ir nevaldomo kraujavimo rizika išlieka. Įprastiniai krešėjimo tyrimai, tokie kaip dalinis aktyvuoto tromboplastino laikas, tarptautinis normalizuotas santykis, trombino laikas tiksliai neatspindi antikoaguliacijos laipsnio NPA vartojantiems ligoniams. Tromboelastografija (TEG) yra vienas iš tyrimo metodų, kuris gali nustatyti antikoaguliacijos laipsnį bei potencialių NPA antidotų efektyvumą. Daugėjant klinikinių studijų apie TEG vaidmenį NPA poveikio bei perdozavimo diagnostikai ir gydymui, šis tyrimas tampa vis svarbesnis klinikinėje praktikoje. ĮvadasVitamino K antagonistai (VKA) ir mažos molekulinės masės heparinai (MMMH) daug metų buvo pagrindiniai medikamentai, skiriami arterinės ir veninės trombozės profilaktikai. VKA būdinga siauras veikimo spektras, nenuspėjami farmakologiniai efektai ir sąveikos su kitais vaistais. Be to, VKA būtinas dažnas krešėjimo rodiklių monitoravimas, o sukeliamos kraujavimo komplikacijos didina juos vartojančių pacientų mirtingumą [1,2]. MMMH yra leidžiami į poodį ir gali sukelti heparino indukuotą trombocitopeniją [3]. Dėl šių priežasčių kuriami nauji antikoaguliantai, kurie būtų saugūs, patogesni vartoti ir turėtų efektyvų farmakologinį poveikį.Naujieji peroraliniai antikoaguliantai (NPA) -dabigatranas, rivaroksabanas, apiksabanas yra pranašesni už senuosius atstovus. Vartojant šiuos vaistus nereikia nuolatinio krešėjimo rodiklių stebėjimo, retos vaistų tarpusavio sąveikos, o parenkant dozę nereikia atsižvelgti į paciento amžių ar svorį [3]. NPA vartoti patogu ir saugu, tačiau sunkios traumos ar kitų kritinių būklių metu ūmaus ir nevaldomo kraujavimo rizika išlieka. Šiuo metu trūksta mokslinių studijų, kurios įvertintų hipokoaguliacijos laipsnį sudėtin-gose klinikinėse situacijose. Efektyvi NPA antagonistinio gydymo strategija klinikinėje praktikoje nėra plačiai ištirta [4]. Tromboelastografija (TEG) yra vienas iš tyrimo metodų, kuris gali nustatyti antikoaguliacijos laispnį bei NPA antagonistų gydymo efektyvumą. Straipsnio tikslas -remiantis mokslinės literatūros duomenimis, apžvelgti NPA veikimo mechanizmus ir TEG vaidmenį monitoruojant NPA poveikį. Išnagrinėjus naujausius literatūros duomenis pateikti diagnostikos naujoves ir gydymo galimybes. Tyrimo objektas ir metodasAtlikta fundamentalių ir klinikinių mokslinių straipsnių apžvalga ir analizė. Ruošiant šį straipsnį paieška buvo vykdoma PubMed, Medline, Cohrane duomenų bazėse. Iš-nagrinėti naujausi straipsniai apie NPA, jų veikimo mechanizmus, skyrimo indikacijas, TEG ir įprastinių krešėjimo sistemos tyrimų pakitimus vartojant NPA. Iš viso išanali-zuota 80 mokslinių darbų, atrinkta 40 aktualiausių mokslinių publikacijų.Dabigatranas. Dabigatranas yra tiesioginis tromb...

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Comparative Metabolism of¹⁴C-Labeled Apixaban in Mice, Rats, Rabbits, Dogs, and Humans

Cited by 101 publications

References 30 publications

In Vitro Assessment of Metabolic Drug-Drug Interaction Potential of Apixaban through Cytochrome P450 Phenotyping, Inhibition, and Induction Studies

In Vitro Assessment of Metabolic Drug-Drug Interaction Potential of Apixaban through Cytochrome P450 Phenotyping, Inhibition, and Induction Studies

Investigating the Enteroenteric Recirculation of Apixaban, a Factor Xa Inhibitor: Administration of Activated Charcoal to Bile Duct-Cannulated Rats and Dogs Receiving an Intravenous Dose and Use of Drug Transporter Knockout Rats

TEG ir naujieji peroraliniai antikoaguliantai

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Comparative Metabolism of14C-Labeled Apixaban in Mice, Rats, Rabbits, Dogs, and Humans

Cited by 101 publications

References 30 publications

In Vitro Assessment of Metabolic Drug-Drug Interaction Potential of Apixaban through Cytochrome P450 Phenotyping, Inhibition, and Induction Studies

In Vitro Assessment of Metabolic Drug-Drug Interaction Potential of Apixaban through Cytochrome P450 Phenotyping, Inhibition, and Induction Studies

Investigating the Enteroenteric Recirculation of Apixaban, a Factor Xa Inhibitor: Administration of Activated Charcoal to Bile Duct-Cannulated Rats and Dogs Receiving an Intravenous Dose and Use of Drug Transporter Knockout Rats

TEG ir naujieji peroraliniai antikoaguliantai

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Comparative Metabolism of¹⁴C-Labeled Apixaban in Mice, Rats, Rabbits, Dogs, and Humans