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<I>In Vitro</I> Biotransformation of the New Oral

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<I>In Vitro</I> Biotransformation of the New Oral ORIGINAL ARTICLES Pharmacokinetics Research Laboratories1, Central Research Laboratories2, Kissei Pharmaceutical Co., Ltd., Nagano; Chemistry Research Laboratories3, Astellas Pharma Inc., Ibaraki; Joetsu Chemical Laboratories4, Kissei Pharmaceutical Co., Ltd., Niigata; Department of Pharmacokinetics and Pharmacodynamics5, Faculty of Pharmaceutical Sciences, Showa University, Tokyo, Japan Characterization of in vitro biotransformation of the new oral anticoagulants, the factor VIIa inhibitors AS1927819-00 and AS1932804-00 T. Nakabayashi 1, Y. Gotoh 2, N. Kamada 2, M. Fujioka 1, T. Ishihara 3, A. Hirabayashi 4, H. Sato 5 Received December 9, 2012, accepted January 4, 2013 Takeshi Nakabayashi, Pharmacokinetics Research Laboratories, Kissei Pharmaceutical Co., Ltd., 19-48 Yoshino, 399-8710, Matsumoto-City, Nagano-Pref takeshi [email protected] Pharmazie 68: 406–413 (2013) doi: 10.1691/ph.2013.2906 We recently developed a prodrug (AS1932804-00, CMP) of the novel FVIIa inhibitor AS1924269-00, which possesses a carbamate amidine backbone. In addition, we developed another type of prodrug (AS1927819- 00, OXP) with an oxime amidine backbone. In this study, we investigated the efficiency of conversion of these novel FVIIa prodrugs to their active forms by evaluating the production of the active form in vitro by using microsomes, mitochondria, and cryopreserved hepatocytes, and compared it with the in vivo conversion mechanisms of the prodrugs (oxime amidine vs. carbamate amidine). We observed that OXP and CMP showed improved oral absorption, and the efficiency of conversion of CMP to the active form was higher than that of OXP. The in vivo rate of conversion of OXP to its active form was low in rats, and compared to liver microsomes and mitochondria, cryopreserved hepatocytes supplemented with serum and coenzymes were an appropriate metabolic test tool. On the other hand, the efficiency of conversion of CMP to its active from could be appropriately evaluated using small intestinal microsomes. The development of a prodrug can be optimized when information about the stability of carboxylic acid esters in the presence of serum esterases, membrane permeability of intermediate forms, and differential tissue specificity to metabolic activities for carbamate and oxime backbones of amidine can be obtained. 1. Introduction Recently developed blood coagulation inhibitors such as sibrafiban (a glycoprotein IIb/IIIa receptor inhibitor) (Wittke Abbreviations: CES, carboxyl esterase; FXa, factor Xa; FVIIa, et al. 1999), ximelagatran (an antithrombin agent) (Eriksson factor VIIa; GP IIb/IIIa, glycoprotein IIb/IIIa; HPLC, high- performance et al. 2003), and dabigatran etexilate (antithrombin agent) (Blech liquid chromatography; LC-MS/MS, liquid chromatography-tandem mass spectrometry; PAMPA, parallel artificial membrane perme- et al. 2008) possess an amidine backbone that retains their ability; AUC, area under the curve; BA, bioavailability; Cmax, inhibitory activities but reduces their extent of oral absorption. maximum plasma concentration; Vss, volume of distribution Therefore, to improve the oral absorption of blood coagula- at steady state; CLtot, total body plasma clearance; T1/2, half tion inhibitors, the hydroxyl or carbamate group was further life; Fa, fraction absorbed; PK, pharmacokinetic; AS1924269-00, introduced at the amidine position and the carboxylic acid was (nominated as ACT) 2-{2-[({2-[(4-Carbamimidoylphenyl)carbamoyl]- esterified. Despite these chemical modifications, the bioavail- 4-methoxyphenyl}amino)methyl]-4-(hydroxymethyl)-6-(propan-2- ability (BA) of the active form was only 10–20% (Eriksson et al. yloxy)phenoxy}acetic acid; AS1928272-00, (nominated as OXI) 2003). 2-(2-{[(2-{[4-(N’-hydroxycarbamimidoyl)phenyl]carbamoyl}-4- Microsomal and mitochondrial metabolism causes a reduction methoxyphenyl)amino]methyl}-4-(hydroxymethyl)-6-(propan-2- of oxime amidine in vitro, and ximelagatran is metabolized to yloxy)phenoxy)acetic acid; AS1927819-00, (nominated as OXP) the active form by reduction in the liver microsomes (Clement Ethyl2-(2-{[(2-{[4-(N’-hydroxycarbamimidoyl)phenyl]carbamoyl}- } et al. 2005; Anderson et al. 2005, Fig. 1). We developed a blood 4-methoxyphenyl)amino]methyl -4-(hydroxymethyl)-6-(propan-2- coagulation inhibitor, AS1924269-00 (ACT), which is a low- yloxy)phenoxy)acetate; AS1937090-FO, (nominated as CMI) 2-[2- molecular-weight amidine compound with an inhibitory effect ({[2-({4-[(Amino[(ethoxycarbonyl)imino]methyl)phenyl]carbamoyl}- 4-methoxyphenyl)amino]methyl}-4-(hydroxymethyl)-6-(propan-2- on FVIIa but has low oral absorption. In this study, we attempted yloxy)phenoxy)acetic acid; AS1932804-00, (nominated as CMP) to develop a prodrug of this compound with improved oral Ethyl2-[2-({[2-({4-[(amino[(ethoxycarbonyl)imino]methyl)phenyl] absorption, as also applied for ximelagatran and dabigatran. carbamoyl}-4- methoxyphenyl)amino]methyl}-4-(hydroxymethyl)- We recently developed a prodrug (AS1932804-00, CMP) of 6-(propan-2-yloxy)phenoxy)acetate KDN-7429 (Internal standard) the novel FVIIa inhibitor (AS1924269-00, ACT), which pos- 2-[4-(Carbamoylmethyl)-2-{[(4-chloro-2-{[4-(N’-hydroxycarbamimidoyl) sesses a carbamate and amidine backbone. The prodrug showed phenyl]carbamoyl}phenyl)-amino]methyl}-6-ethoxyphenoxy]acetic acid ;. 406 Pharmazie 68 (2013) ORIGINAL ARTICLES Fig. 1: Metabolic pathways of ximelagatran. Ximelagatran is converted to hydroxymelagatran and ethylmelagatran, and subsequently, these metabolites are converted to melagatran increased Caco-2 membrane permeability and oral absorption and small amounts were produced from OXP. In contrast, we in rats. The BA of the ACT was only 0.3%, but that after oral observed marked conversion of CMP to its active form. administration of a carbamate prodrug (CMP) was 36.1%, which When the oxime amidine prodrugs, ximelagatran and OXP,were suggested that the carbamate prodrug was rapidly hydrolyzed to added to rat cryopreserved hepatocytes, the concentration of its active form after oral absorption (Nakabayashi et al. 2013). the active form measured after 1, 2, and 4 h showed a time- In this study, we investigated the efficiency of conversion of the novel FVIIa prodrugs to their active forms by evaluating the in vitro production of the active form using microsomes, mito- Table1: In vitro bioactivation of OXP, CMP, and ximelagatran chondria, and cryopreserved hepatocytes, and we compared the to theparent amidine drug by hepatic microsomes and in vivo conversion mechanisms of the different prodrugs (oxime mitochondria of the ratwith NADH or NADPH amidine vs. carbamate amidine) to the in vitro mechanisms. Source Cofactor Conversion rate (pmol/min/mg) [a] 2. Investigation and results OXP Microsome NADH 46.6 ± 7.2 NADPH 35 ± 2.2 2.1. In vitro experiments Mitochondria NADH 218 ± 5.4 The active form of ximelagatran (i.e., melagatran) was produced NADPH 135 ± 3.5 in the liver microsomes and mitochondria of the rat at a rate CMP Microsome NADH ND of 50–120 pmol/min/mg (Table 1). AS1927819-00 (OXP) was NADPH ND metabolized in the liver microsomes and mitochondria to gen- Mitochondria NADH ND erate its active form; the rates of production of the active form NADPH ND Ximelagatran Microsome NADH 124 ± 2.9 were equivalent to or higher than those of ximelagatran in both ± rat liver microsomes and mitochondria. In contrast, no active NADPH 100 3.5 Mitochondria NADH 81 ± 7.5 form of the carbamate amidine prodrug, CMP, was detected in NADPH 53.6 ± 2.9 the liver microsomes or mitochondria. We also investigated the production of the active form in small OXP, AS1927819-00; CMP, AS1932804-00 intestinal microsomes of the rat (Table 2). No active form [a] Conversion rates are means ± standard deviation (SD) of 3 determinations was produced from an oxime amidine prodrug, ximelagatran, ND, not detectable Pharmazie 68 (2013) 407 ORIGINAL ARTICLES dependent increase, and the rate of production of the active form from OXP was faster than that from ximelagatran (Table 3). In the presence of serum, the rate of active form production was higher in ximelagatran, whereas the active form was only weakly produced from OXP. In contrast, no active form was detected in cryopreserved hepatocytes of the rat treated with CMP. 2.2. In vivo experiments The time-course of blood levels after the oral administration of ximelagatran, OXP, and CMP at 10 mg/kg to rats is shown in Fig. 2, and the pharmacokinetic parameters are shown in Table 4–1. After oral administration of ximelagatran, its active form, melagatran, was mainly detected, and the BAs of the active form and the intermediate (hydroxymelagatran) were 7.0% and 1.2%, respectively. The area under the curve (AUC) of the intermediate and active form as a percentage of the total AUC (conversion rate) was 85%. For OXP, the intermediate (OXI) was mainly detected. The BAs of OXI and the active form (ACT) were 32.2% and 4.0%, respectively, and the conversion rate was Fig.3: Pharmacokinetics profiles of ACT (AS1924269-00) and melagatran after intravenous administration to rats. Symbols and vertical bars represent the about 11%. The AUCs of OXI and the active form were 47.0 mean ± standard deviation (SD) from 3 rats. The vertical bars are not shown and 6.07 ␮mol·h/L, respectively. when SD falls within the symbol. The AUC of the active form after the oral administration of ximelagatran was 3.12 ␮mol·h/L, and that for OXP was ␮ · An oxime amidine prodrug, ximelagatran, was converted to its 6.07 mol h/L, which indicated that OXP surpassed ximelaga- active form
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