Polymorphic Expression of Cyp1a2 Leading to Interindividual Variability in Metabolism of a Novel Benzodiazepine Receptor Partial Inverse Agonist in Dogs

Mise, Masashi; Yadera, Seiji; Matsuda, Michiaki; Hashizume, Takanori; Matsumoto, Satoshi; Terauchi, Yoshiaki; Fujii, Toshihiko

doi:10.1124/dmd.32.2.240

Cited by 39 publications

(32 citation statements)

References 21 publications

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“…This expectation is reinforced by the similarity in inhibitory effects of anti-human CYP1A2 antibodies and ␣-naphthoflavone, a CYP1A2 inhibitor, on the metabolism of YM-64227. POD is known to be a human and canine CYP1A2 activity marker (Kobayashi et al, 1997;Shimada et al, 1997), and ␣-naphthoflavone inhibits POD both in canine and human liver microsomes (Nakajima et al, 1999;Mise et al, 2004b). As is shown in Fig.…”

Section: Discussionmentioning

confidence: 71%

“…These findings suggested that CYP1A2 plays a significant role in the formation of MM-2 and MM-3, but not in the formation of others. ␣-Naphthoflavone, a typical CYP1A2 inhibitor (Chang et al, 1994;Mise et al, 2004b), reduced the MM-2 and MM-3 formation rates in the C/C and C/T types, but no inhibitory effects were observed in the T/T type. Thus, the metabolic activities of MM-2 and MM-3 in the presence of ␣-naphthoflavone were comparable in the three types.…”

Section: Discussionmentioning

confidence: 99%

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Elucidation of the Effects of the CYP1A2 Deficiency Polymorphism in the Metabolism of 4-Cyclohexyl-1-ethyl-7-methylpyrido[2,3-d]pyrimidine-2-(1H)-one (YM-64227), a Phosphodiesterase Type 4 Inhibitor, and Its Metabolites in Dogs

Tenmizu

Noguchi²,

Kamimura³

2006

Drug Metab Dispos

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ABSTRACT:The canine CYP1A2 1117 C>T single nucleotide polymorphism is responsible for a substantial portion of the interindividual variability seen in the pharmacokinetics of 4-cyclohexyl-1-ethyl-7-methylpyrido[2,3-d]pyrimidine-2-(1H)-one (YM-64227). The purpose of this study is to investigate the contribution of CYP1A2 to the metabolism of YM-64227 and its five metabolites (MM-1 to MM-5), as well as to determine the interindividual variability between the pharmacokinetic profiles of the compounds with respect to the CYP1A2 deficiency polymorphism. ␣-Naphthoflavone and anti-CYP1A1/2 antibody inhibited the metabolic activities at which MM-2 and MM-3 were formed from YM-64227 in C/C-and C/T-type microsomes. In T/T type, the rate of MM-2 and MM-3 formation was lower, and ␣-naphthoflavone and anti-CYP1A1/2 antibody were shown to have no effect. A positive correlation between the overall metabolism of YM-64227 and phenacetin O-deethylation, a CYP1A2 activity marker, was observed in all the genotypes. The in vitro metabolic clearances in the T/T type of MM-1, MM-3, MM-4, and MM-5 were less than 50% lower than those in the C/C type. The anti-CYP1A1/2 antibody inhibited the metabolism of MM-1, MM-3, MM-4, and MM-5 in the C/C and C/T types. These results suggest that the formation of MM-2 and MM-3 from YM-64227 is catalyzed by CYP1A2, and that CYP1A2 contributes mainly to the subsequent metabolism of the primary metabolites of YM-64227, with the exception of MM-2. It is possible that the interindividual variability of YM-64227 with respect to the CYP1A2 deficiency polymorphism is caused by a decrease in the metabolic activities of both the unchanged drug and its metabolites. 4-) is a novel phosphodiesterase type 4 inhibitor. Unlike other phosphodiesterase type 4 inhibitors, YM-64227 does not induce the emetic effects that normally accompany the anti-inflammatory activity. In addition, it maintains the ability to inhibit antigen-induced airway responses. For this reason, YM-64227 promises to be a highly effective and safe drug when used as an antiasthmatic or antiinflammatory drug (Iwata et al., 1998).In previous studies, a novel CYP1A2 1117 CϾT single nucleotide polymorphism (SNP) was found in beagle dogs, which are used extensively in pharmacology and safety assessment studies (Tenmizu et al., 2004a;Mise et al., 2004a). This SNP resulted in an amino acid change from an Arg codon to a stop codon at position 373, yielding an inactive enzyme. The T-allele frequency was 0.39, which suggests that 10 to 15% of the dogs would not express the CYP1A2 protein. This CYP1A2 deficiency polymorphism causes significant changes in the pharmacokinetic profile of YM-64227 in beagle dogs (Tenmizu et al., 2006). The plasma concentrations of the unchanged drug and five of its metabolites (MM-1 to MM-5, Fig. 1) were determined after both intravenous and oral administration of YM-64227 to genotyped dogs (C/C, C/T, and T/T groups). After a single oral administration, the maximum plasma concentration and absolute bioavailability of YM-64227 in ...

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Section: Discussionmentioning

confidence: 71%

Section: Discussionmentioning

confidence: 99%

Elucidation of the Effects of the CYP1A2 Deficiency Polymorphism in the Metabolism of 4-Cyclohexyl-1-ethyl-7-methylpyrido[2,3-d]pyrimidine-2-(1H)-one (YM-64227), a Phosphodiesterase Type 4 Inhibitor, and Its Metabolites in Dogs

Tenmizu

Noguchi²,

Kamimura³

2006

Drug Metab Dispos

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“…Although our study demonstrates a trend toward a decline in acetaminophen production, a less than 2-fold difference was observed between the CYP1A2-deficient and wildtype groups; whereas Mise et al (2004b) and Tenmizu et al (2006) observed 5.2-and 24.7-fold differences in oral exposure of unchanged drug between TT and CC dogs. In summary, in vivo studies were conducted to assess the metabolic disposition of phenacetin and formation of acetaminophen in dogs having normal CYP1A2 activity versus those deficient in CYP1A2 activity.…”

Section: Phenacetin Pharmacokinetics In Cyp1a2-deficient Dogsmentioning

confidence: 65%

“…Despite the fact that a greater difference in the acetaminophen/ phenacetin ratio was observed after a 5 mg/kg dose of phenacetin, thus supporting the saturation theory, the lower phenacetin dose still did not produce a robust difference in overall acetaminophen produced compared with the CYP1A2 substrates studied by Mise et al (2004b) and Tenmizu et al (2006). Although our study demonstrates a trend toward a decline in acetaminophen production, a less than 2-fold difference was observed between the CYP1A2-deficient and wildtype groups; whereas Mise et al (2004b) and Tenmizu et al (2006) observed 5.2-and 24.7-fold differences in oral exposure of unchanged drug between TT and CC dogs.…”

Section: Phenacetin Pharmacokinetics In Cyp1a2-deficient Dogsmentioning

confidence: 72%

“…The mutation is a single nucleotide polymorphism, CYP1A2 1117 CϾT, which results in an amino acid change from arginine to an early stop codon at position 373 (truncated inactive protein). Pharmacokinetic variability was observed in dogs after administration of 5-(3-methoxyphenyl)-3-(5-methyl-1,2,4-oxadiazol-3-yl)-2-oxo-1,2-dihydro-1,6-naphthyridine (AC-3933) and 4-cyclohexyl-1-ethyl-7-methylpyrido[2,3-d]pyrimidine-2-(1H)-one (YM-64227), both metabolized primarily by CYP1A2 (Mise et al, 2004b;Tenmizu et al, 2006). In CYP1A2-deficient dogs (TT), AC-3933 and YM-64227 exhibited 5.2-and 24.7-fold higher mean oral exposures (AUC) of parent drug, respectively, compared with wild-type or heterozygous dogs.…”

Section: Introductionmentioning

confidence: 99%

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Phenacetin Pharmacokinetics in CYP1A2-Deficient Beagle Dogs

Whiterock

Morgan²,

Lentz³

et al. 2011

Drug Metab Dispos

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ABSTRACT:Phenacetin is widely used as an in vitro probe to measure CYP1A2 activity across species. To investigate whether phenacetin can be used as an in vivo probe substrate to phenotype CYP1A2 activity in dogs, beagle dogs previously genotyped for a single nucleotide polymorphism that yields an inactive CYP1A2 protein were selected and placed into one of three groups: CC (wild-type), CT (heterozygous), or TT (homozygous mutants). The dogs were dosed with phenacetin orally at 5 and 15 mg/kg and intravenously at 15 mg/kg. Plasma samples were analyzed by liquid chromatography-tandem mass spectrometry, and phenacetin and its primary metabolite, acetaminophen, were monitored. After intravenous dosing, all groups showed similar exposure of phenacetin irrespective of genotype. After oral dosing at 15 mg/kg, the exposure of phenacetin in CC and CT dogs was similar, but phenacetin exposure was 2-fold greater in TT dogs. Exposure of the metabolite, acetaminophen, was similar in all groups; however, the mean acetaminophen/phenacetin ratio in TT dogs was 1.7 times less than that observed in CC dogs. Similar trends between the groups of dogs with respect to phenacetin exposure were also observed after a lower 5 mg/kg p.o. dose of phenacetin; however, a proportionally greater amount of acetaminophen was generated. Although oral exposure of phenacetin was 2-fold higher and acetaminophen exposure was 2-fold lower in CYP1A2-deficient (TT) dogs, these results were considered modest and suggest that phenacetin is not a selective or robust in vivo probe to measure CYP1A2 enzyme activity in the dog. IntroductionCytochrome P450 (P450) enzymes play a significant role in the oxidative metabolism and elimination of xenobiotics and endogenous substances. P450 enzymes have been extensively studied in humans and rodents; however, dogs are commonly used for pharmacological and absorption, distribution, metabolism, and excretion/toxicology studies of new drug candidates, and studies of their P450 enzymes and polymorphisms are few (Tenmizu et al., 2006;Zhou et al., 2010). Although genetic polymorphisms have been reported in the dog, our understanding of their contribution to the interindividual variability in drug pharmacokinetics related to pharmaceutical drug development and veterinary practice is limited (Mise et al., 2004a).The CYP1A2 enzyme is expressed in all mammals with few species differences in function or regulation, and all have very similar amino acid sequences (Parkinson and Ogilvie, 2008). In humans, CYP1A2 polymorphisms in the coding region are rare and only occasionally appear to decrease enzyme activity (Faber et al., 2005). A CYP1A2 polymorphism in beagle dogs has been reported (Tenmizu et al., 2004). The mutation is a single nucleotide polymorphism, CYP1A2 1117 CϾT, which results in an amino acid change from arginine to an early stop codon at position 373 (truncated inactive protein). Pharmacokinetic variability was observed in dogs after administration of 5-(3-methoxyphenyl)-3-(5-methyl-1,2,4-oxadiazol-3-yl)-2-oxo-1,2-d...

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