Abstract:
:The mRNA levels of human cytochrome P450 (CYP)2Cs and CYP3As in primary cultures of freshly isolated human hepatocytes were assessed after exposure to NO-1886 and rifampicin, a typical inducer of CYP3As. mRNA levels were analyzed by real-time RT-PCR using an ABI PRISM 7700 Sequence Detector system. Exposure to NO-1886 for 24 hr at a concentration of less than 10 microM showed only a tendency to reduce or increase the expression levels of CYP2C8, CYP2C9, CYP2C19, CYP3A4, or CYP3A5 mRNA. A higher concentration (50 microM) of NO-1886 induced an increase in CYP2C8 mRNA and a decrease in CYP2C19 mRNA, and these changes continued after additional culture for 24 hr in fresh medium without NO-1886. The expression level of CYP3A4 mRNA after exposure to NO-1886 for 24 hr at 50 microM was about twice that in controls. Following additional culture for 24 hr in fresh medium without NO-1886, the expression of CYP3A4 mRNA was comparable to that in controls. On the other hand, the expression levels of CYP2C9 and CYP3A5 mRNA showed small and variable changes in each donor even at a high concentration (50 microM) of NO-1886. Furthermore, the pharmacokinetics of NO-1886 during repeated oral administration for 14 days was studied in female rats. The pharmacokinetic parameters of NO-1886 were nearly the same on days 1, 7, and 14 of repeated administration. The hepatic microsomal content of CYP isoforms was not affected by repeated administration for 7 days at a dose of 1 to 30 mg/kg in female rats, although the total CYP content was increased at a dose of 30 mg/kg. The expression levels of CYP1A2, CYP2B2, CYP2C12, and CYP2E1 mRNA in primary cultures of rat hepatocytes were not affected by exposure to NO-1886 at 2, 10, or 50 microM. The expression levels of CYP3A1 mRNA in primary cultures of rat hepatocytes were not affected by exposure to NO-1886 at 2 or 10 microM, but were increased, with large individual variation, by exposure at 50 microM. The mRNA expression levels in rat hepatocytes exposed to concentrations comparable to free plasma levels did not change significantly, which was consistent with the equivalence in the in vivo plasma concentrations observed on days 1 and 14 of repeated administration. These results suggest that repeated administration of NO-1886 at clinical doses does not significantly affect the expression levels of CYP isoforms in human liver, although the mRNA levels of the CYP isoforms involved in the metabolism of NO-1886 were increased by exposure to higher concentrations of NO-1886 in human hepatocytes in vitro.
journal_name
Drug Metab Pharmacokinetjournal_title
Drug metabolism and pharmacokineticsauthors
Morioka Y,Nishimura M,Imai T,Suzuki S,Harada M,Satoh T,Naito Sdoi
10.2133/dmpk.21.19subject
Has Abstractpub_date
2006-02-01 00:00:00pages
19-28issue
1eissn
1347-4367issn
1880-0920pii
JST.JSTAGE/dmpk/21.19journal_volume
21pub_type
杂志文章abstract::The enzyme activities of CYP2D6 and CYP2C19 show a genetic polymorphism, and the frequency of poor metabolizers (PMs) on these enzymes depends on races. We have analyzed frequencies of mutant alleles and PMs based on the published data in previous study (Shimizu, T. et al.: Bioinformatics research on inter-racial diff...
journal_title:Drug metabolism and pharmacokinetics
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abstract::Polymorphic human and cynomolgus macaque flavin-containing monooxygenases (FMO) 3 are important oxygenation enzymes for nitrogen-containing drugs. Inter-animal variability of FMO3-dependent drug oxygenations in vivo is suspected in cynomolgus macaques because such variability is evident in humans. Therefore, this foll...
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abstract::Chemotherapy-induced neutropenia is one of the major adverse events which results in the reduction of chemotherapy. Doxorubicin is a substrate of the adenosine triphosphate-binding cassette subfamily B member 1 (ABCB1) transporter; reportedly, ABCB1 polymorphisms influence doxorubicin pharmacokinetics. We evaluated th...
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abstract::The objectives of this study were to develop a population pharmacokinetic model of imidafenacin and to explore the factors that affect the pharmacokinetics of imidafenecin. A total of 2406 plasma samples were collected from 90 healthy volunteers and 457 patients with overactive bladder. We determined the plasma concen...
journal_title:Drug metabolism and pharmacokinetics
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journal_title:Drug metabolism and pharmacokinetics
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journal_title:Drug metabolism and pharmacokinetics
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journal_title:Drug metabolism and pharmacokinetics
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journal_title:Drug metabolism and pharmacokinetics
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journal_title:Drug metabolism and pharmacokinetics
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journal_title:Drug metabolism and pharmacokinetics
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journal_title:Drug metabolism and pharmacokinetics
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journal_title:Drug metabolism and pharmacokinetics
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doi:10.2133/dmpk.dmpk-10-sc-036
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journal_title:Drug metabolism and pharmacokinetics
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journal_title:Drug metabolism and pharmacokinetics
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pub_type: 杂志文章,随机对照试验
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journal_title:Drug metabolism and pharmacokinetics
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abstract::The interaction between cytochrome P450s (CYP, P450) and UDP-glucuronosyltransferases (UGTs) was studied by co-immunoprecipitation. P450 isoform-selective antibody was used as a probe to co-precipitate UGTs with the P450s from solubilized rat liver microsomes. Antibodies toward CYP3A2, CYP2B2, CYP2C11/13 and CYP1A2 co...
journal_title:Drug metabolism and pharmacokinetics
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journal_title:Drug metabolism and pharmacokinetics
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journal_title:Drug metabolism and pharmacokinetics
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