Simultaneous determination of YM‐64227, a phosphodiesterase type 4 inhibitor, and its ﬁve metabolites in dog plasma by high‐performance liquid chromatography with ﬂuorescence detection

Tenmizu, Daisuke; Fukunaga, Yasuhisa; Noguchi, Kaoru; Kamimura, Hidetaka

doi:10.1002/bmc.371

Cited by 4 publications

(4 citation statements)

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“…Plasma was stored frozen at Ϫ20°C until it was analyzed to determine the concentrations of YM-64227 and its metabolites. Concentrations of YM-64227 and its metabolites were quantified using HPLC (Tenmizu et al, 2004b). In brief, sample preparation used the liquid-liquid extraction using tert-butyl methyl ether.…”

Section: Methodsmentioning

confidence: 99%

THE CANINE CYP1A2 DEFICIENCY POLYMORPHISM DRAMATICALLY AFFECTS THE PHARMACOKINETICS OF 4-CYCLOHEXYL-1-ETHYL-7-METHYLPYRIDO[2,3-D]-PYRIMIDINE-2-(1H)-ONE (YM-64227), A PHOSPHODIESTERASE TYPE 4 INHIBITOR

et al. 2006

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ABSTRACT:In a previous study, it was shown that the novel canine single nucleotide polymorphism (SNP) CYP1A2 1117C>T yields an inactive enzyme. In this study, the effect that this SNP has on the pharmacokinetics of 4-cyclohexyl-1-ethyl-7-methylpyrido[2,3-d]pyrimidine-2-(1H)-one (YM-64227) was investigated. Plasma concentrations of the unchanged drug and five of its metabolites (MM-1 to MM-5) were determined after either intravenous or oral administration of YM-64227 to genotyped dogs (C/C, C/T, and T/T groups). Liver microsomes were prepared from these dogs to determine the in vitro metabolic clearance of YM-64227. After a single oral administration, the maximum plasma concentration and absolute bioavailability of YM-64227 in the T/T group were 17.1 times and 27.2 times higher than those in the C/C group, respectively, whereas the pharmacokinetics of YM-64227 after intravenous administration were not affected by genotype. The metabolic profiles in the T/T group were quite distinct from the others; i.e., the main metabolite was MM-2 in the C/C group, whereas MM-1 and MM-5 were the main metabolites in the T/T group. The formation clearances of MM-2 and MM-3 in the microsomes derived from T/T type dogs were significantly lower, whereas those of MM-1, MM-4, and MM-5 were not affected. A statistically significant correlation was observed between the in vivo and in vitro metabolic intrinsic clearances (r ‫؍‬ 0.82, p < 0.001). The canine CYP1A2 1117C>T SNP proved to be responsible for a substantial portion of the interindividual variability in the pharmacokinetics of YM-64227.Cytochrome P450 (P450) is a superfamily of enzymes that plays an important role in the oxidative metabolism of a wide variety of xenobiotics as well as endogenous compounds (Nelson et al., 1996). The metabolic activity of P450 is affected by several factors such as inhibition by concomitant drugs, induction, and genetic polymorphism (Pelkonen et al., 1998). The P450 polymorphisms have been investigated extensively in clinical settings, and it is well known that mutated alleles of CYP2C9, CYP2C19, and CYP2D6 cause altered plasma concentrations, which might in turn cause unforeseeable adverse reactions (Kagimoto et al., 1990;Sullivan-Klose et al., 1996;Furuta et al., 1999).A large number of P450 cDNA clones have been isolated, sequenced, and extensively studied in humans, mice, and rats (http:// drnelson.utmem.edu/CytochromeP450.html). On the other hand, only a few studies on canine P450 cDNAs have been conducted, although dogs are used extensively in pharmacological research and drug safety assessment studies. At present, a variety of canine P450 enzymes such et al., 1991;Fraser et al., 1997) have been cloned and sequenced. Although gene analysis has revealed that some of these P450s have variants, no obvious change in the plasma concentration of drug associated with single nucleotide polymorphisms (SNPs) has been reported for dogs. In fact, only a few studies have shown the possibility that interindividual variations in the pharmacokinetics of so...

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Section: Methodsmentioning

confidence: 99%

THE CANINE CYP1A2 DEFICIENCY POLYMORPHISM DRAMATICALLY AFFECTS THE PHARMACOKINETICS OF 4-CYCLOHEXYL-1-ETHYL-7-METHYLPYRIDO[2,3-D]-PYRIMIDINE-2-(1H)-ONE (YM-64227), A PHOSPHODIESTERASE TYPE 4 INHIBITOR

et al. 2006

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“…Blood (about 5 ml) was collected from the forelimb vein using a heparinized syringe after 0.5 h. Concentrations of YM-64227 and MM-2 were quantified by high-performance liquid chromatography (Tenmizu et al 2004). In brief, the plasma samples were extracted with tert-butyl methyl ether under alkali conditions.…”

Section: Phenotypingmentioning

confidence: 99%

Identification of the novel canine CYP1A2 1117 C>T SNP causing protein deletion

Tenmizu¹,

Endo²,

Noguchi³

et al. 2004

Xenobiotica

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1. The pharmacokinetics of YM-64227 (4-cyclohexyl-1-ethyl-7-methylpyrido[2,3-d]-pyrimidine-2-(1H)-one), a novel and selective phosphodiesterase type 4 inhibitor, was characterized in beagle dogs. Based on the plasma parent drug to major hydroxylated metabolite ratio, 21 dogs were phenotyped as 16 extensive metabolizers (EM) and five poor metabolizers (PM).2. Nucleotide sequences of CYPs 1A2, 2B11, 2C21, 2D15, 2E1 and 3A12 were investigated in the EM and PM dogs. A CYP1A2 1117 C>T single nucleotide polymorphism was found, which resulted in an amino acid change from an Arg codon to a stop codon at position 373.

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“…Tenmizu et al (2004) have developed an HPLC fluorescence assay for the quantitation of YM-64227, a novel and selective PDE4 inhibitor, and five of its pharmacologically active hydroxylated metabolites in dog plasma. Since both in vitro and in vivo metabolism/ biotransformation work has demonstrated the occurrence of five phydroxylated metabolites of YM-64227 with PDE4 inhibition properties, it was important to evaluate the pharmacokinetic and toxicokinetic disposition of all the metabolites.…”

Section: Case Studiesmentioning

confidence: 99%

Applicability of bioanalysis of multiple analytes in drug discovery and development: review of select case studies including assay development considerations

Srinivas

2006

Biomed. Chromatogr.

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The development of sound bioanalytical method(s) is of paramount importance during the process of drug discovery and development culminating in a marketing approval. Although the bioanalytical procedure(s) originally developed during the discovery stage may not necessarily be fit to support the drug development scenario, they may be suitably modified and validated, as deemed necessary. Several reviews have appeared over the years describing analytical approaches including various techniques, detection systems, automation tools that are available for an effective separation, enhanced selectivity and sensitivity for quantitation of many analytes. The intention of this review is to cover various key areas where analytical method development becomes necessary during different stages of drug discovery research and development process. The key areas covered in this article with relevant case studies include: (a) simultaneous assay for parent compound and metabolites that are purported to display pharmacological activity; (b) bioanalytical procedures for determination of multiple drugs in combating a disease; (c) analytical measurement of chirality aspects in the pharmacokinetics, metabolism and biotransformation investigations; (d) drug monitoring for therapeutic benefits and/or occupational hazard; (e) analysis of drugs from complex and/or less frequently used matrices; (f) analytical determination during in vitro experiments (metabolism and permeability related) and in situ intestinal perfusion experiments; (g) determination of a major metabolite as a surrogate for the parent molecule; (h) analytical approaches for universal determination of CYP450 probe substrates and metabolites; (i) analytical applicability to prodrug evaluations-simultaneous determination of prodrug, parent and metabolites; (j) quantitative determination of parent compound and/or phase II metabolite(s) via direct or indirect approaches; (k) applicability in analysis of multiple compounds in select disease areas and/or in clinically important drug-drug interaction studies. A tabular representation of select examples of analysis is provided covering areas of separation conditions, validation aspects and applicable conclusion. A limited discussion is provided on relevant aspects of the need for developing bioanalytical procedures for speedy drug discovery and development. Additionally, some key elements such as internal standard selection, likely issues of mass detection, matrix effect, chiral aspects etc. are provided for consideration during method development.

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Simultaneous determination of YM‐64227, a phosphodiesterase type 4 inhibitor, and its ﬁve metabolites in dog plasma by high‐performance liquid chromatography with ﬂuorescence detection

Cited by 4 publications

References 11 publications

THE CANINE CYP1A2 DEFICIENCY POLYMORPHISM DRAMATICALLY AFFECTS THE PHARMACOKINETICS OF 4-CYCLOHEXYL-1-ETHYL-7-METHYLPYRIDO[2,3-D]-PYRIMIDINE-2-(1H)-ONE (YM-64227), A PHOSPHODIESTERASE TYPE 4 INHIBITOR

THE CANINE CYP1A2 DEFICIENCY POLYMORPHISM DRAMATICALLY AFFECTS THE PHARMACOKINETICS OF 4-CYCLOHEXYL-1-ETHYL-7-METHYLPYRIDO[2,3-D]-PYRIMIDINE-2-(1H)-ONE (YM-64227), A PHOSPHODIESTERASE TYPE 4 INHIBITOR

Identification of the novel canine CYP1A2 1117 C>T SNP causing protein deletion

Applicability of bioanalysis of multiple analytes in drug discovery and development: review of select case studies including assay development considerations

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