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Intestinal and hepatic expression of cytochrome P450s and mdr1a in rats with indomethacin-induced small intestinal ulcers.

Kawauchi S, Nakamura T, Yasui H, Nishikawa C, Miki I, Inoue J, Horibe S, Hamaguchi T, Tanahashi T, Mizuno S - Int J Med Sci (2014)

Bottom Line: Gene expression of the CYP family of enzymes and mdr1a was measured with quantitative real-time polymerase chain reaction (qPCR).Although previous studies have shown a direct effect of INM on CYP3A activity, we could not confirm any change in hepatic CY3A4 expression (major isoform of human CYP3A) in vitro.INM-induced SIUs had a subtle effect on intestinal CYP expression, but had an apparent action on hepatic CYP, which was influenced, at least in part, by the secondary inflammation.

View Article: PubMed Central - PubMed

Affiliation: 1. Department of Medical Pharmaceutics, Kobe Pharmaceutical University, 4-19-1 Motoyamakita-machi, Higashinada-ku, Kobe, 658-8558, Japan; ; 2. Educational Center for Clinical Pharmacy, Kobe Pharmaceutical University, 4-19-1 Motoyamakita-machi, Higashinada-ku, Kobe, 658-8558, Japan;

ABSTRACT

Background: Non-steroidal anti-inflammatory drugs induce the serious side effect of small intestinal ulcerations (SIUs), but little information is available regarding the consequences to drug metabolism and absorption.

Aim: We examined the existence of secondary hepatic inflammation in rats with indomethacin (INM)-induced SIUs and assessed its relationship to the cytochrome P450 (CYP) and P-glycoprotein (mdr1a), the major drug-metabolizing factors in the small intestine and the liver.

Methods: Gene expression of the CYP family of enzymes and mdr1a was measured with quantitative real-time polymerase chain reaction (qPCR). Vancomycin (VCM), a poorly absorbed drug, was administered intraduodenally to rats with SIUs.

Results: INM induced SIUs predominantly in the lower region of the small intestine with high expression of inflammatory markers. Liver dysfunction was also observed, which suggested a secondary inflammatory response in rats with SIUs. In the liver of rats with SIUs, the expression of CYP2C11, CYP2E1, and CYP3A1 was significantly decreased, and loss of CYP3A protein was observed. Although previous studies have shown a direct effect of INM on CYP3A activity, we could not confirm any change in hepatic CY3A4 expression (major isoform of human CYP3A) in vitro. The plasma VCM concentration was increased in rats with SIUs due to partial absorption from the mucosal injury, but not in normal mucosa.

Conclusions: INM-induced SIUs had a subtle effect on intestinal CYP expression, but had an apparent action on hepatic CYP, which was influenced, at least in part, by the secondary inflammation. Furthermore, drug absorption was increased in rats with SIUs.

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Plasma concentration of VCM in rats with INM-induced SIUs. VCM was administered intraduodenally at a dose of 500 mg/kg after treatment with INM or vehicle. Venous blood was collected at 10, 20, 30, 45, 60, 90, and 120 min after the administration of VCM. VCM plasma concentration-time profiles were constructed from concentrations measured by HPLC, as described in Materials and Methods. Data were obtained for each individual rat in the control (open symbols; N = 4) and SIU (closed symbols; N = 5) groups.
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Figure 7: Plasma concentration of VCM in rats with INM-induced SIUs. VCM was administered intraduodenally at a dose of 500 mg/kg after treatment with INM or vehicle. Venous blood was collected at 10, 20, 30, 45, 60, 90, and 120 min after the administration of VCM. VCM plasma concentration-time profiles were constructed from concentrations measured by HPLC, as described in Materials and Methods. Data were obtained for each individual rat in the control (open symbols; N = 4) and SIU (closed symbols; N = 5) groups.

Mentions: Figure 7 shows the concentration-time profiles of VCM after intraduodenal administration in rats with INM-induced SIU. VCM was detected in the plasma in three out of five rats with SIUs. Among the three rats in which plasma VCM could be detected, the concentration of VCM gradually increased up to 120 min in two rats, but only a transient increase was observed in the remaining one. The highest value of plasma VCM was 4.8 μg/ml at 120 min after administration, and the calculated AUC0-120 ranged from 14.7 to 362.0 μg∙min/ml. In the control, there was no detectable plasma concentration of VCM.


Intestinal and hepatic expression of cytochrome P450s and mdr1a in rats with indomethacin-induced small intestinal ulcers.

Kawauchi S, Nakamura T, Yasui H, Nishikawa C, Miki I, Inoue J, Horibe S, Hamaguchi T, Tanahashi T, Mizuno S - Int J Med Sci (2014)

Plasma concentration of VCM in rats with INM-induced SIUs. VCM was administered intraduodenally at a dose of 500 mg/kg after treatment with INM or vehicle. Venous blood was collected at 10, 20, 30, 45, 60, 90, and 120 min after the administration of VCM. VCM plasma concentration-time profiles were constructed from concentrations measured by HPLC, as described in Materials and Methods. Data were obtained for each individual rat in the control (open symbols; N = 4) and SIU (closed symbols; N = 5) groups.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4196121&req=5

Figure 7: Plasma concentration of VCM in rats with INM-induced SIUs. VCM was administered intraduodenally at a dose of 500 mg/kg after treatment with INM or vehicle. Venous blood was collected at 10, 20, 30, 45, 60, 90, and 120 min after the administration of VCM. VCM plasma concentration-time profiles were constructed from concentrations measured by HPLC, as described in Materials and Methods. Data were obtained for each individual rat in the control (open symbols; N = 4) and SIU (closed symbols; N = 5) groups.
Mentions: Figure 7 shows the concentration-time profiles of VCM after intraduodenal administration in rats with INM-induced SIU. VCM was detected in the plasma in three out of five rats with SIUs. Among the three rats in which plasma VCM could be detected, the concentration of VCM gradually increased up to 120 min in two rats, but only a transient increase was observed in the remaining one. The highest value of plasma VCM was 4.8 μg/ml at 120 min after administration, and the calculated AUC0-120 ranged from 14.7 to 362.0 μg∙min/ml. In the control, there was no detectable plasma concentration of VCM.

Bottom Line: Gene expression of the CYP family of enzymes and mdr1a was measured with quantitative real-time polymerase chain reaction (qPCR).Although previous studies have shown a direct effect of INM on CYP3A activity, we could not confirm any change in hepatic CY3A4 expression (major isoform of human CYP3A) in vitro.INM-induced SIUs had a subtle effect on intestinal CYP expression, but had an apparent action on hepatic CYP, which was influenced, at least in part, by the secondary inflammation.

View Article: PubMed Central - PubMed

Affiliation: 1. Department of Medical Pharmaceutics, Kobe Pharmaceutical University, 4-19-1 Motoyamakita-machi, Higashinada-ku, Kobe, 658-8558, Japan; ; 2. Educational Center for Clinical Pharmacy, Kobe Pharmaceutical University, 4-19-1 Motoyamakita-machi, Higashinada-ku, Kobe, 658-8558, Japan;

ABSTRACT

Background: Non-steroidal anti-inflammatory drugs induce the serious side effect of small intestinal ulcerations (SIUs), but little information is available regarding the consequences to drug metabolism and absorption.

Aim: We examined the existence of secondary hepatic inflammation in rats with indomethacin (INM)-induced SIUs and assessed its relationship to the cytochrome P450 (CYP) and P-glycoprotein (mdr1a), the major drug-metabolizing factors in the small intestine and the liver.

Methods: Gene expression of the CYP family of enzymes and mdr1a was measured with quantitative real-time polymerase chain reaction (qPCR). Vancomycin (VCM), a poorly absorbed drug, was administered intraduodenally to rats with SIUs.

Results: INM induced SIUs predominantly in the lower region of the small intestine with high expression of inflammatory markers. Liver dysfunction was also observed, which suggested a secondary inflammatory response in rats with SIUs. In the liver of rats with SIUs, the expression of CYP2C11, CYP2E1, and CYP3A1 was significantly decreased, and loss of CYP3A protein was observed. Although previous studies have shown a direct effect of INM on CYP3A activity, we could not confirm any change in hepatic CY3A4 expression (major isoform of human CYP3A) in vitro. The plasma VCM concentration was increased in rats with SIUs due to partial absorption from the mucosal injury, but not in normal mucosa.

Conclusions: INM-induced SIUs had a subtle effect on intestinal CYP expression, but had an apparent action on hepatic CYP, which was influenced, at least in part, by the secondary inflammation. Furthermore, drug absorption was increased in rats with SIUs.

Show MeSH
Related in: MedlinePlus