Differences in the pharmacokinetics of Cyp3a substrates in TSOD and streptozotocin-induced diabetic mice

Kudo, Toshiyuki; Toda, Takahiro; Ushiki, Takashi; Ohi, Kanna; Ikarashi, Nobutomo; Ochiai, Wataru; Sugiyama, Kiyoshi

doi:10.3109/00498251003596809

Cited by 21 publications

(20 citation statements)

References 26 publications

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“…Similar rises of the CYP3A‐related metabolism (Kudo et al. ) and mRNA transcription were also described and proved to be CAR‐mediated (Dong et al. ).…”

Section: Resultssupporting

confidence: 59%

Modulation of CYP3a expression and activity in mice models of type 1 and type 2 diabetes

Patoine

Petit

Pilote

et al. 2014

Pharmacology Res & Perspec

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CYP3A4, the most abundant cytochrome P450 enzyme in the human liver and small intestine, is responsible for the metabolism of about 50% of all marketed drugs. Numerous pathophysiological factors, such as diabetes and obesity, were shown to affect CYP3A activity. Evidences suggest that drug disposition is altered in type 1 (T1D) and type 2 diabetes (T2D). The objective was to evaluate the effect of T1D and T2D on hepatic and intestinal CYP3a drug-metabolizing activity/expression in mice. Hepatic and intestinal microsomes were prepared from streptozotocin-induced T1D, db/db T2D and control mice. Domperidone was selected as a probe substrate for CYP3a and formation of five of its metabolites was evaluated using high performance liquid chromatography. Hepatic CYP3a protein and mRNA expression were assessed by Western blot and reverse-transcription quantitative polymerase chain reaction respectively. Hepatic microsomal CYP3a activity was significantly increased in both T1D and T2D groups versus control group. Intestinal CYP3a activity was also significantly increased in both T1D and T2D groups. Moreover, significant increases of both hepatic CYP3a mRNAs and protein expression were observed in both T1D and T2D groups versus control group. Additional experiments with testosterone further validated the increased activity of CYP3a under the effect of both T1D and T2D. Although differences exist in the pathophysiological insults associated with T1D and T2D, our results suggest that these two distinct diseases may have the same modulating effect on the regulation of CYP3a, ultimately leading to variability in drug response, ranging from lack of effect to life-threatening toxicity.

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“…Similar rises of the CYP3A‐related metabolism (Kudo et al. ) and mRNA transcription were also described and proved to be CAR‐mediated (Dong et al. ).…”

Section: Resultssupporting

confidence: 59%

Modulation of CYP3a expression and activity in mice models of type 1 and type 2 diabetes

Patoine

Petit

Pilote

et al. 2014

Pharmacology Res & Perspec

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“…Therefore, it is possible that high-fat diet causes lifestyle that affects the pharmacokinetics of CYP3A substrates. 9,10) However, the possibility that the continuous intake of a highfat diet by itself could change the expression level of CYP3A and affect the pharmacokinetics of a CYP3A substrate is considered to be low. In addition, the enteric environment was altered when the animals were fed different diets, which triggered changes in the expression level and activity of CYP3A in the liver.…”

Section: Discussionmentioning

confidence: 99%

“…The residue was dissolved in the HPlC mobile phase [acetonitrile : methanol : 10 mm potassium phosphate buffer (3 : 6 : 11, pH 7.4)], and HPlC-UV was used to quantify 4-hydroxytriazolam and α-hydroxytriazolam. 10,23) The initial linear rate conditions have been confirmed with respect to microsomal protein concentration (up to 1 mg/ml) and incubation time (up to 40 min).…”

Section: Methodsmentioning

confidence: 99%

“…7,8) In addition, it has been demonstrated that the expression level and activity of CYP3A are affected by diseases including diabetes mellitus. 9,10) Recently, it has been reported that the expression levels of CYPs are also altered in response to the intake of fatty acids 11,12) and vitamins. 13,14) It is obvious that the expression and activity of CYPs are affected by various factors.…”

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confidence: 99%

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Different Diets Cause Alterations in the Enteric Environment and Trigger Changes in the Expression of Hepatic Cytochrome P450 3A, a Drug-Metabolizing Enzyme

Tajima

Ikarashi

Igeta

et al. 2013

Biological & Pharmaceutical Bulletin

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Changes in the expression level and activity of cytochrome P450 (CYP) in the liver are caused by various factors and affect the pharmacokinetics of drugs. The purpose of this study was to determine whether the expression of CYP3A is affected by a high-fat diet. In addition, we examined whether the type of diet given to mice could produce changes in the expression level and activity of CYP3A. Mice were fed a purified diet containing 10 kcal% lard (control group) or 60 kcal% lard (HF group) or regular mouse chow containing 13 kcal% of fat (MF group) for 4 weeks. No significant differences were observed in the hepatic CYP3A protein expression level between the HF group and the control group. The CYP3A protein expression in the MF group was significantly higher than that observed in the control group. In the MF group, the area under the curve (AUC) of intraperitoneally administered triazolam was lower. Because lithocholic acid (LCA) is known to increase hepatic CYP3A expression, the levels of Clostridium sordellii and LCA in the feces were measured. In the MF group, the levels of Clostridium sordellii and LCA were higher. It has been demonstrated that a high-fat diet does not cause any changes in hepatic CYP3A expression. In addition, the different diets caused alterations in the enteric environment, which triggered changes in CYP3A expression. Therefore, it is necessary to carefully consider the type of feed while performing animal experiments to evaluate the pharmacokinetics of drugs.

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“…The authors, therefore, proposed that the differences in insulin plasma levels could result in alterations of the expression of the small intestinal CYP3A between the two types of DM. This, in turn, can cause different pharmacokinetics of drugs in IDDM (type 1) and NIDDM (type 2) [34].…”

Section: Animal Studiesmentioning

confidence: 99%

Effect of Diabetes Mellitus on the Metabolism of Drugs and Toxins

Houshang¹

2015

J Clin Toxicol

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Diabetes mellitus (DM) is a complicated endocrine disorder that can clinically impair tissues and organs due to hyperglycemia. One of the areas of concern in diabetes would be the higher amount of medications being consumed by diabetes sufferers that is the corollary of its inevitable complications such as micro-and macro-vascular damages to various organs. Different metabolic pathways are involved in the biotransformation of drugs and toxins, thus their pharmacokinetic/toxicokinetic can be affected by DM primarily due to changes in enzymes and drug transporters. On the other hand, different enzymatic pathways are involved in the metabolic processes of substances. While not many human studies are available, several investigations have been carried out in animal models of diabetes, the majority of them being rodents. Given the high prevalence of DM and its important complications, the effect of this disease on the metabolism of some of the toxins and drugs is discussed herein.

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Differences in the pharmacokinetics of Cyp3a substrates in TSOD and streptozotocin-induced diabetic mice

Cited by 21 publications

References 26 publications

Modulation of CYP3a expression and activity in mice models of type 1 and type 2 diabetes

Modulation of CYP3a expression and activity in mice models of type 1 and type 2 diabetes

Different Diets Cause Alterations in the Enteric Environment and Trigger Changes in the Expression of Hepatic Cytochrome P450 3A, a Drug-Metabolizing Enzyme

Effect of Diabetes Mellitus on the Metabolism of Drugs and Toxins

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