Metabolism and Pharmacokinetics of a Dipeptidyl Peptidase Iv Inhibitor in Rats, Dogs, and Monkeys With Selective Carbamoyl Glucuronidation of the Primary Amine in Dogs

ABSTRACT:The pharmacokinetics, excretion, and metabolism of milnacipran were evaluated after oral administration of a 100-mg dose of [ 14 C]milnacipran hydrochloride to healthy male subjects. The peak plasma concentration of unchanged milnacipran (ϳ240 ng/ml) was attained at 3.5 h and was lower than the peak plasma concentration of radioactivity (ϳ679 ng Eq of milnacipran/ml) observed at 4.3 h, indicating substantial metabolism of milnacipran upon oral administration. Milnacipran has two chiral centers and is a racemic mixture of cis isomers: d-milnacipran (1S, 2R) and l-milnacipran (1R, 2S). After oral administration, the radioactivity of almost the entire dose was excreted rapidly in urine (approximately 93% of the dose). Approximately 55% of the dose was excreted in urine as unchanged milnacipran, which contained a slightly higher proportion of d-milnacipran (ϳ31% of the dose). In addition to the excretion of milnacipran carbamoyl O-glucuronide metabolite in urine (ϳ19% of the dose), predominantly as the l-milnacipran carbamoyl O-glucuronide metabolite (ϳ17% of the dose), approximately 8% of the dose was excreted in urine as the N-desethyl milnacipran metabolite. No additional metabolites of significant quantity were excreted in urine. Similar plasma concentrations of milnacipran and the l-milnacipran carbamoyl O-glucuronide metabolite were observed after dosing, and the maximum plasma concentration of l-milnacipran carbamoyl O-glucuronide metabolite at 4 h after dosing was 234 ng Eq of milnacipran/ml. Lower plasma concentrations (<25 ng Eq of milnacipran/ml) of N-desethyl milnacipran and dmilnacipran carbamoyl O-glucuronide metabolites were observed.

Section: Discussionmentioning

confidence: 99%

Excretion and Metabolism of Milnacipran in Humans after Oral Administration of Milnacipran Hydrochloride

Chin

Wangsa

et al. 2012

“…at ASPET Journals on May 11, 2018 dmd.aspetjournals.org Downloaded from primary amine was reported for the dipeptidyl peptidase inhibitors L-threo isoleucine thiazolidide and its allo stereoisomer (Beconi et al, 2003) and seems to be common for a group of low molecular weight amino amides.…”

Section: Disposition Of Sitagliptin In Rats and Dogsmentioning

confidence: 99%

“…3) of m/z 628 produced sequential loss of glucuronic acid (176 amu) and carbon dioxide (44 amu) to give m/z of 452 and 408, respectively. This is a typical fragmentation pattern for a carbamoyl glucuronic acid conjugate (Liu and Pereira, 2002;Beconi et al, 2003). …”

Section: Disposition Of Sitagliptin In Rats and Dogsmentioning

confidence: 99%

Disposition of the Dipeptidyl Peptidase 4 Inhibitor Sitagliptin in Rats and Dogs

Beconi¹,

Reed²,

Teffera³

et al. 2007

Self Cite

ABSTRACT:The pharmacokinetics, metabolism, and excretion of sitagliptin The plasma clearance and volume of distribution of sitagliptin were higher in rats (40-48 ml/min/kg, 7-9 l/kg) than in dogs (ϳ9 ml/min/kg, ϳ3 l/kg), and its half-life was shorter in rats, ϳ2 h compared with ϳ4 h in dogs. Sitagliptin was absorbed rapidly after oral administration of a solution of the phosphate salt. The absolute oral bioavailability was high, and the pharmacokinetics were fairly dose-proportional. After administration of [ 14 C]sitagliptin, parent drug was the major radioactive component in rat and dog plasma, urine, bile, and feces. Sitagliptin was eliminated primarily by renal excretion of parent drug; biliary excretion was an important pathway in rats, whereas metabolism was minimal in both species in vitro and in vivo. Approximately 10 to 16% of the radiolabeled dose was recovered in the rat and dog excreta as phase I and II metabolites, which were formed by N-sulfation, N-carbamoyl glucuronidation, hydroxylation of the triazolopiperazine ring, and oxidative desaturation of the piperazine ring followed by cyclization via the primary amine. The renal clearance of unbound drug in rats, 32 to 39 ml/min/kg, far exceeded the glomerular filtration rate, indicative of active renal elimination of parent drug.Dipeptidyl peptidase 4 (DPP-4) is a ubiquitous proline-specific serine protease responsible for the rapid inactivation of the incretin glucagon-like peptide 1 (GLP-1) (Mentlein et al., 1993;Gorrell, 2005). GLP-1 and GLP-1 analogs have been shown to decrease fasting and postprandial glucose in diabetic patients when given as a continuous intravenous infusion or by subcutaneous administration (Zander et al., 2002;Gautier et al., 2005). The effectiveness of orally administered DPP-4 inhibitors has been demonstrated in obese Zucker rats (Balkan et al., 1999;Pospisilik et al., 2002), mice (Mu et al., 2006, and humans (Ahren et al., 2004;Herman et al., 2004Herman et al., , 2005aScott et al., 2005;Cornell, 2006). Thus, stabilization of GLP-1 via DPP-4 inhibition represents a new therapeutic approach for type 2 diabetes (Drucker, 2006;Green et al., 2006).Sitagliptin ( (Fig. 1), is a potent and selective, reversible inhibitor of DPP-4 with an IC 50 value of 18 nM (Kim et al., 2005). Sitagliptin has been shown to inhibit plasma DPP-4 activity in normal volunteers (Herman et al., 2005a;Bergman et al., 2006) and in patients with type 2 diabetes (Herman et al., 2004), and to significantly reduce HbA 1c and fasting plasma glucose in patients with type 2 diabetes (Herman et al., 2005b;Scott et al., 2005). In support of the suitability of the rat and dog as toxicology species, the disposition of sitagliptin was evaluated in these species and compared with that in humans. Results from in vitro (rat, dog, human) and in vivo studies in rats and dogs are discussed herein. The absorption, metabolism, and excretion of sitagliptin in humans are reported in the accompanying article . Materials and MethodsChemicals and Reagents. Sitagliptin was prep...

“…The first, Ma, an N-carbamoyl glucuronide metabolite found in all species except humans, was presumably formed by reaction of the amine with dissolved CO 2 to form a transient carbamic acid intermediate, followed by subsequent conjugation with glucuronic acid. N-carbamoyl glucuronidation is an uncommon metabolic reaction but has been reported for several primary and secondary amines, including tocainide (Elvin et al, 1980), carvedilol (Schaefer, 1992), a dipeptidyl peptidase IV inhibitor ILT-threo (Beconi et al, 2003), and sertraline (Obach et al, 2005). In vitro formation of N-carbamoyl glucuronide metabolites have also been reported in liver microsomes incubated in a CO 2 -rich atmosphere and in carbonate buffer in the presence of UDP-GA. Obach et al (2005) have also reported that sertraline N-carbamoyl glucuronidation was primarily formed by UGT2B7.…”

Section: Discussionmentioning

confidence: 94%

In Vitro Metabolism of the Novel, Highly Selective Oral Angiogenesis Inhibitor Motesanib Diphosphate in Preclinical Species and in Humans

Kuchimanchi²,

Hickman³

et al. 2009

ABSTRACT:Motesanib diphosphate is a novel, investigational, highly selective oral inhibitor of the receptor tyrosine kinases vascular endothelial growth factor receptors 1, 2, and 3, the platelet-derived growth factor receptor, and the stem cell factor receptor (Kit). The in vitro metabolic profiles of [ 14 C]motesanib were examined by using microsomes and hepatocytes from preclinical species and humans. Several oxidative metabolites were observed and characterized by tandem mass spectrometry, nuclear magnetic resonance spectroscopy, and coinjection with authentic standards. Cytochrome P450 (P450) 3A4 is the major isozyme involved in the oxidative biotransformation of motesanib, but the CYP2D6 and CYP1A isozymes also make minor contributions. In hepatocyte incubations, oxidative and conjugative pathways were observed for all species examined, and indoline N-glucuronidation was the dominant pathway. Three less common and novel phase II conjugates of the indoline nitrogen were detected in hepatocytes and in microsomes supplemented with specific cofactors, including N-carbamoyl glucuronide, N-glucose, and N-linked ␤-N-acetylglucosamine. An N-glucuronide metabolite was the most frequently observed phase II conjugate in liver microsomes of all species, whereas the N-acetylglucosamine conjugate was observed only in monkey liver microsomes. Incubations with recombinant human UDP-glucuronosyltransferases (UGTs) and inhibition by the UGT1A4 and UGT1A1 substrates/inhibitors imipramine and bilirubin suggested that UGT1A4 is the major UGT isozyme catalyzing the N-glucuronidation of motesanib, with a minor contribution from UGT1A1. The in vitro metabolic profiles were similar between the human and preclinical species examined. All metabolites found in humans were also detected in other species.Motesanib diphosphate (formerly known as AMG 706) (Fig. 1) is a highly selective kinase inhibitor with both antiangiogenic and direct antitumor activity (Polverino et al., 2006;Rosen et al., 2007). Motesanib is an ATP-competitive inhibitor of vascular endothelial growth factor (VEGF) receptors 1, 2, and 3, platelet-derived growth factor (PDGF) receptor, and stem cell factor receptor (Kit), which have all been implicated in the pathogenesis of human tumors (Dvorak, 2002;Heinrich et al., 2002;Song et al., 2005). In preclinical models of human cancer, oral administration of motesanib potently inhibited VEGF-induced angiogenesis in the rat corneal model and induced regression of established A431 xenografts (Polverino et al., 2006). Furthermore, motesanib has shown antiangiogenic and antitumor activity in patients with advanced solid malignancies (Rosen et al., 2007). Additional studies of motesanib as monotherapy and in combination with various agents are currently ongoing.Definitive characterization of metabolites and examination of species differences in metabolism are becoming increasingly important.