Intestinal Expression and Metabolic Activity of the CYP3A Subfamily in Female Rats

Aiba, Tetsuya; Yoshinaga, Mariko; Ishida, Kazuya; Takehara, Yutaka; Hashimoto, Yoshiaki

doi:10.1248/bpb.28.311

Cited by 30 publications

(26 citation statements)

References 21 publications

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“…The baseline levels of CYP3A1 and CYP3A2 protein in liver microsomes were 28.95 pmol/mg and 48.60 pmol/mg, respectively, and this result was consistent with the values previously reported in the literature [40] . Experiments from previous studies showed significant induction of CYP3A1 and CYP3A2 proteins in rats treated with the same dose of DEX [41,42] , which is similar to the results obtained in the present study.…”

Section: Discussionsupporting

confidence: 92%

A mechanism-based pharmacokinetic/pharmacodynamic model for CYP3A1/2 induction by dexamethasone in rats

Deng

et al. 2012

Acta Pharmacol Sin

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Aim: To develop a pharmacokinetic/pharmacodynamic (PK/PD) model describing the receptor/gene-mediated induction of CYP3A1/2 by dexamethasone (DEX) in rats. Methods: A group of male Sprague-Dawley rats receiving DEX (100 mg/kg, ip) were sacrificed at various time points up to 60 h posttreatment. Their blood sample and liver were collected. The plasma concentration of DEX was determined with a reverse phase HPLC method. CYP3A1/2 mRNA, protein levels and enzyme activity were measured using RT-PCR, ELISA and the testosterone substrate assay, respectively. Data analyses were performed using a first-order conditional estimate (FOCE) with INTERACTION method in NON-MEM version 7.1.2. Results: A two-compartment model with zero-order absorption was applied to describe the pharmacokinetic characteristics of DEX. Systemic clearance, the apparent volume of distribution and the duration of zero-order absorption were calculated to be 172.7 mL·kg --1 ·h -1 , 657.4 mL/kg and 10.47 h, respectively. An indirect response model with a series of transit compartments was developed to describe the induction of CYP3A1/2 via PXR transactivation by DEX. The maximum induction of CYP3A1 and CYP3A2 mRNA levels was achieved, showing nearly 21.29-and 8.67-fold increases relative to the basal levels, respectively. The CYP3A1 and CYP3A2 protein levels were increased by 8.02-fold and 2.49-fold, respectively. The total enzyme activities of CYP3A1/2 were shown to increase by up to 2.79-fold, with a lag time of 40 h from the Tmax of the DEX plasma concentration. The final PK/PD model was able to recapitulate the delayed induction of CYP3A1/2 mRNA, protein and enzyme activity by DEX. Conclusion: A mechanism-based PK/PD model was developed to characterize the complex concentration-induction response relationship between DEX and CYP3A1/2 and to resolve the drug-and system-specific PK/PD parameters for the course of induction.

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Section: Discussionsupporting

confidence: 92%

A mechanism-based pharmacokinetic/pharmacodynamic model for CYP3A1/2 induction by dexamethasone in rats

Deng

et al. 2012

Acta Pharmacol Sin

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“…These data suggest that Cyp2a2 and Cyp3a9 may be important for NMBA metabolism in rat esophagus, and they may be targets for PEITC inhibition. These observations require confirmation in further studies, however, because both genes have been reported to be expressed predominately in the liver (37,38). Interestingly, as reported earlier by our laboratory, treatment with NMBA did not result in significant changes in the expression of the Cyp2a3 gene in the rat esophagus, suggesting that Cyp2a3 is either noninducible or its constitutive levels are sufficient for metabolism of NMBA in the esophagus.…”

Section: Discussionsupporting

confidence: 79%

Effects of Phenylethyl Isothiocyanate on Early Molecular Events in N-Nitrosomethylbenzylamine–Induced Cytotoxicity in Rat Esophagus

et al. 2007

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There is little information on early molecular events in the development of N -nitrosomethylbenzylamine (NMBA)-induced rat esophageal tumorigenesis and of the effects of chemopreventive agents on these events. In this study, we identified genes in rat esophagus that were differentially expressed in response to short-term NMBA treatment and modulated by cotreatment with phenylethyl isothiocyanate (PEITC). Rats were fed AIN-76A diet or AIN-76A diet containing PEITC for 3 weeks. During the 3rd week of dietary treatment, they were administered three s.c. doses of NMBA (0.5 mg/kg body weight). Rats were sacrificed 24 h after the last treatment; esophagi were excised and processed for histologic grading, microarray and real-time PCR analysis. Histopathologic analysis showed that treatment of rats with PEITC had a protective effect on NMBA-induced preneoplastic lesions in the rat esophagus. We identified 2,261 genes that were differentially expressed in the NMBA-treated versus control esophagi and 1,936 genes in the PEITC + NMBA versus NMBA-treated esophagi. The intersection of these two sets resulted in the identification of 1,323 genes in NMBA-treated esophagus, the vast majority of which were modulated by PEITC to near-normal levels of expression. Measured changes in the expression levels of eight selected genes were validated using real-time PCR. Results from 12 microarrays indicated that PEITC treatment had a genome-wide modulating effect on NMBA-induced gene expression. Samples obtained from animals treated with PEITC alone or cotreated with PEITC + NMBA were more similar to controls than to samples treated with NMBA alone. [Cancer Res 2007;67(13):6484-92]

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“…Sexdependent differences in xenobiotic metabolism in rats can largely be attributed to differences in the profile of cytochrome P450 isoforms found in male and female liver and intestine (Martignoni et al, 2006). In fact, the isoforms CYP3A2 and CYP3A9 in rat are, respectively, related to androgens and estrogen secretion, at least in liver if not in the intestine (Aiba et al, 2005), whereas CYP3A18 and CYP3A23 are constantly higher in males (Mahnke et al, 1997). The 10 to 30% less total cytochrome P450 expression in females as opposed to that in males (Mugford and Kedderis, 1998) could explain the slower casopitant metabolism observed in females, resulting in lower clearance and higher concentrations of the parent compound observed in both plasma and liver.…”

Section: Discussionmentioning

confidence: 99%

Metabolic Disposition of Casopitant, a Potent Neurokinin-1 Receptor Antagonist, in Mice, Rats, and Dogs

Miraglia

Pagliarusco²,

Bordini³

et al. 2010

Drug Metab Dispos

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species: the maximum plasma concentration of radioactivity was generally observed 0.5 to 2 h after a single oral dose. In dog and female rat, as observed for humans, the principal circulating radiolabeled components were unchanged casopitant and its hydroxylated derivative M13. In rats, there was an evident sex-related difference in the rate of elimination of drug-related material with elimination being more rapid in males than in females. In dogs and mice, no notable sex differences were observed in the pattern of excretion. The elimination of drug-related radioactivity was largely by metabolism, with metabolites excreted primarily in the feces. The predominant route of metabolism was the oxidation of the parent molecule, observed together with loss of the Nacetyl group, N-demethylation, and modification of piperazine with consequent opening and cleavage of the ring, giving a complex pattern of metabolites. Conjugation of some of those oxidized products with glucuronic acid was observed. Urinary excretion in all three species was a minor route of elimination, accounting for between 2 and 7% of the dose, with unchanged parent drug never quantifiable.

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Intestinal Expression and Metabolic Activity of the CYP3A Subfamily in Female Rats

Cited by 30 publications

References 21 publications

A mechanism-based pharmacokinetic/pharmacodynamic model for CYP3A1/2 induction by dexamethasone in rats

A mechanism-based pharmacokinetic/pharmacodynamic model for CYP3A1/2 induction by dexamethasone in rats

Effects of Phenylethyl Isothiocyanate on Early Molecular Events in N-Nitrosomethylbenzylamine–Induced Cytotoxicity in Rat Esophagus

Metabolic Disposition of Casopitant, a Potent Neurokinin-1 Receptor Antagonist, in Mice, Rats, and Dogs

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