Application of the PKCYP-test to Predict the Amount of in Vivo CYP2C11 Using Tolbutamide as a Probe.

Matsunaga, Noriko; Nishijima, Taeko; Hattori, Kenji; Iizasa, Hisashi; Yamamoto, Keiko; Kizu, Junko; Takanaka, Akira; Morikawa, Atsushi; Nakashima, Emi

doi:10.1248/bpb.24.1305

Cited by 9 publications

(14 citation statements)

References 19 publications

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“…71 CCl 4 -treated rats have been used as models for low levels of CYP2C11 in the liver. 72 Other examples include Lgals3 73,74 In addition, there were many novel changes in gene expression documented by this study. Many of the observed expression changes for these genes appeared to correlate with the known functional roles of the genes and, in some cases, could be linked with other genes affected by CCl 4 .…”

Section: Discussionmentioning

confidence: 64%

Analysis of gene expression in carbon tetrachloride-treated rat livers using a novel bioarray technology

et al. 2003

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The present study successfully utilizes a new ADME Rat Expression Bioarray, containing 1040 metabolism-and toxicology-linked genes, to monitor gene expression from the livers of rats treated with carbon tetrachloride (CCl 4 ). Histopathological analysis, hierarchical clustering methods, and gene expression profiling are compared between the control and CCl 4 -treated animals. A total of 44 transcripts were found to be altered in response to the hepatotoxin, 19 of which were upregulated and 25 were downregulated. Some of these gene expression changes were expected and concurred with previously published data while others were novel findings.

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Section: Discussionmentioning

confidence: 64%

Analysis of gene expression in carbon tetrachloride-treated rat livers using a novel bioarray technology

et al. 2003

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“…The CYP2C family (2C6 or 2C11) is responsible for the hepatic metabolism of tolbutamide in rats (Azuma et al, 1999;Matsunaga et al, 2001). We found much weaker tolbutamide hydroxylation activity in OM microsomes than in hepatic microsomes; among the tested substrates, tolbutamide was the least metabolized molecule in OM.…”

Section: Downloaded Frommentioning

confidence: 70%

Characterization of Microsomal Cytochrome P450-Dependent Monooxygenases in the Rat Olfactory Mucosa

Minn¹,

Pelczar²,

Denizot³

et al. 2005

Drug Metab Dispos

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ABSTRACT:Nasal administration of a drug ensures therapeutic action by rapid systemic absorption and/or the entry of some molecules into the brain through different routes. Many recent studies have pointed out the presence of xenobiotic-metabolizing enzymes in rat olfactory mucosa (OM). Nevertheless, very little is known about the precise identity of isoforms of cytochrome P450 (P450)-dependent monooxygenases (P450) and their metabolic function in this tissue. Therefore, we evaluated mRNA expression of 19 P450 isoforms by semiquantitative reverse transcriptase-polymerase chain reaction and measured their microsomal activity toward six model substrates. For purposes of comparison, studies were conducted on OM and the liver. Specific activities toward phenacetin, chlorzoxazone, and dextromethorphan are higher in OM than in the liver; those toward lauric acid and testosterone are similar in both tissues, and that toward tolbutamide is much lower in OM. There are considerable differences between the two tissues with regard to mRNA expression of P450 isoforms. Some isoforms are expressed in OM but not in the liver (CYP1A1, 2G1, 2B21, and 4B1), whereas mRNA of others (CYP2C6, 2C11, 2D2, 3A1, 3A2, and 4A1) is present only in hepatic tissue. Although expression of CYP1A2, 2A1, 2A3, 2B2, 2D1, 2D4, 2E1, 2J4, and 3A9 is noticed in both tissues, there are a number of quantitative differences. On the whole, our results strongly suggest that CYP1A1, 1A2, 2A3, 2E1, 2G1, and 3A9 are among the main functional isoforms present in OM, at least regarding activities toward the six tested substrates. The implication of olfactory P450-dependent monooxygenases in toxicology, pharmacology, and physiology should be further investigated.

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“…We prepared model rats with various degrees of acute hepatic failure induced by administering various doses of CCl 4 . To examine the degree of CL tot decrease in acute hepatic failure, we selected eight probe drugs which are metabolized by various CYP isoforms: caffeine 25) by CYP1A2, doxorubicin 26) by CYP2B1, tolbutamide 27) by CYP2C11, chlorzoxazone 28) by CYP2E1, and cyclosporine A, 29) lidocaine, 30) tacrolimus 29) and zonisamide 31) by CYP3A2. We found that the blood or plasma concentrations of these drugs in CCl 4 -treated rats were significantly higher than those in control rats (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Plasma was separated by centrifugation at 3000ϫg for 10 min and stored at Ϫ30°C. The HPLC assays for caffeine, 17) chlorzoxazone, 18,19) doxorubicin, 20) lidocaine, 21) tolbutamide 22) and zonisamide 23) were carried out according to the cited methods. The blood concentration of cyclosporin A or tacrolimus was measured with a TDx or an IMx analyzer using a commercial assay kit (Tacrolimus II, Dainabot Co., Ltd., Tokyo, Japan), according to the manufacturer's instructions.…”

Section: Materials Adriacin Injectionmentioning

confidence: 99%

Serum Aminotransferase Activity as a Predictor for Estimation of Total Clearance of Hepatically Metabolized Drugs in Rats with Acute Hepatic Failure

Yokogawa

Ido

Kurihara

et al. 2006

Biological & Pharmaceutical Bulletin

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In treating patients with hepatic failure, it is necessary to set an appropriate drug dosing schedule to take into account of their altered drug disposition kinetics. However, little work has been done to estimate the decrease of total clearance (CL tot ) in relation to the degree of residual hepatic function. Therefore, there is great need for a suitable marker to quantitatively predict the hepatic metabolic capacity in patients with hepatic failure.In humans, there are five predominant families of cytochrome P450 (CYP) species, CYP1A, CYP2C, CYP2D, CYP2E and CYP3A; all of the isoforms differ in their patterns of drug-metabolizing activity, 1) and the amounts of the isoforms in the liver are altered under conditions of hepatic failure.2) The drug-metabolizing activity of the liver may be evaluated on the basis of the correlation between the clearance and the ratio of the metabolite(s) to unchanged drug after the administration of specific inhibitors of various CYP isoforms.Recently, there have been many reports on the expression levels of CYP isoform mRNAs in human liver collected by hepatobiopsy, but no clear correlation has been found between expression levels and the degree of hepatic failure. 3,4) Finnstrom et al. reported that the expression of CYP mRNA in liver is different from that in blood; therefore, blood cannot serve as a surrogate organ for assessment of the expression of the CYP genes in liver.5) Panduro et al. 6) reported that liver regeneration and fibrosis are related to g-carboxylase activity, which is associated with a prolongation of prothrombin time in plasma in rats treated with CCl 4 . Clinically, indocyanine green is commonly used to assess hepatic function. 7)However, none of these procedures appears to be suitable for predicting the decrease in hepatic metabolic activity in patients with hepatic failure.It has been proposed that the drug-metabolizing activity of the liver can be estimated by means of pharmacokinetic analysis after the administration of various probe drugs for CYP isoforms. [8][9][10][11] Matsuo et al. demonstrated that there is a correlation between the CL tot of cyclosporine and the grade severity of liver disease by Child-Pugh classification in patients with hepatitis. 12) However, it is not easy to utilize these approaches to determine the degree of residual hepatic metabolizing ability in patients, as is also the case with creatinine clearance in patients with renal failure.We previously reported that there is a good correlation between mRNA expression and enzyme activity of various CYP isoforms in the livers of rats with acute hepatic failure induced by various doses of CCl 4 . 13) In that study, we also found a good negative correlation between serum aminotransferase activity (AST) and the hepatic activity of each CYP isoform, though the degree of decrease of CL tot varied markedly among CYP isoforms.Here, we present a novel procedure to predict the decrease of CL tot , including that for unknown drugs, based on an increase in serum AST activity in rats with ac...

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Application of the PKCYP-test to Predict the Amount of in Vivo CYP2C11 Using Tolbutamide as a Probe.

Cited by 9 publications

References 19 publications

Analysis of gene expression in carbon tetrachloride-treated rat livers using a novel bioarray technology

Analysis of gene expression in carbon tetrachloride-treated rat livers using a novel bioarray technology

Characterization of Microsomal Cytochrome P450-Dependent Monooxygenases in the Rat Olfactory Mucosa

Serum Aminotransferase Activity as a Predictor for Estimation of Total Clearance of Hepatically Metabolized Drugs in Rats with Acute Hepatic Failure

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