Modulation of mdr1a and CYP3A gene expression in the intestine and liver as possible cause of changes in the cyclosporin A disposition kinetics by dexamethasone

Yokogawa, Koiçhi; Shimada, Tsutomu; Higashi, Yasuhiko; Itoh, Yoshie; Masue, Toshiko; Ishizaki, Junko; Asahi, Mariko; Miyamoto, Ken‐ichi

doi:10.1016/s0006-2952(01)00911-x

Cited by 45 publications

(38 citation statements)

References 32 publications

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“…We designed that AMB is administered with 1.5 or 3.0 mg/kg to rats because total clearance of AMB of rats is about 5-times higher than that of human (0.5 mg/kg) [21]. As we previously clarified that dexamethasone [9] and cyclophosphamide [10] within 4 days after the co-administration induce P-gp and CYP3A2, in this study the AMB co-administerd intravenously to rats for 4 days. (Table 1).…”

Section: Discussionmentioning

confidence: 99%

“…This would be consistent with the relatively minor renal impairment. The studies with DEX [9][10][11]26] indicated that increased mRNA levels of mdr1a, mdr1b…”

Section: Discussionmentioning

confidence: 99%

“…P-gp and/or CYP3A limit the oral bioavailability of digoxin [4], rifampin [4], vinblastine [5], dextromethorphan [6] and CyA [7,8]. We have already shown that the blood concentration of CyA is reduced by pretreatment with dexamethasone [9], cyclophosphamide [10] or levothyroxine [11] in rats, owing to induction of P-gp and CYP3A2 in liver and intestine. In those reports, we demonstrated that the oral bioavailability of CyA is primarily controlled by the level of CYP3A in the upper small intestine under physiological conditions, whereas after treatment with inducers, P-gp in the upper intestine also plays a significant role as an absorption barrier to CyA.…”

Section: Introductionmentioning

confidence: 99%

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Mechanism of decrease of oral bioavailability of cyclosporin A during immunotherapy upon coadministration of amphotericin B

Ishizaki

Ito

Jin

et al. 2008

Biopharm & Drug Disp

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Running Title: Interaction of oral cyclosporin A/amphotericin B Abbreviations: CyA, cyclosporin A; AMB; amphotericin B; BA, bioavailability; CYP, cytochrome P450; P-gp, P-glycoprotein; DEX, dexamethasone; ALT, alanine aminotransferase; AST, aspartate aminotransferase; γ-GTP, γ-glutamyltranspeptidase; BUN, blood urea nitrogen; AUC 0-24h , area under the blood concentration-time curve from 0 to 24 h; MRT, mean residence time; CL tot , total clearance; Vd ss , distribution volume at the steady-state -1-ABSTRACT: The trough level of blood concentration of cyclosporin A (CyA) in a patients receiving immunotherapy was observed to decrease following coadministration of amphotericin B (AMB). We confirmed this clinical observation in experiments using Wistar rats intravenously given AMB (1.5 or 3.0 mg/kg) or saline (control) for 4 days, followed by CyA (10 mg/kg). The blood concentration of CyA after iv or po administration in both AMB groups was significantly decreased compared with the control. The oral bioavailability of CyA after 1.5 or 3.0 mg/kg AMB treatment was decreased to 67 or 46%, respectively, of that of the control group. AMB treatment increased the expression levels of mdr1a and mdr1b mRNAs in duodenum to about 3 times the control, and expression of CYP3A2 mRNA in liver was increased to about twice the control. The induction of their mRNAs by AMB treatment increased the level of P-gp and CYP3A2 protein to about twice the control. These findings suggest that the oral bioavailability of CyA is reduced as a result of both increased efflux transport via P-glycoprotein in the duodenum and an increased firstpass effect of CYP3A2-mediated hepatic metabolic activity, induced by AMB. We suggest that careful monitoring of CyA levels is necessary in the event of AMB administration to patients receiving immunotherapy with CyA.

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Section: Discussionmentioning

confidence: 99%

“…This would be consistent with the relatively minor renal impairment. The studies with DEX [9][10][11]26] indicated that increased mRNA levels of mdr1a, mdr1b…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mechanism of decrease of oral bioavailability of cyclosporin A during immunotherapy upon coadministration of amphotericin B

Ishizaki

Ito

Jin

et al. 2008

Biopharm & Drug Disp

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“…Immunoblotting of the microsomes for CYP2E1 and b-actin was carried out essentially as described by Yokogawa et al [18]. The microsomal protein was resolved by 10% SDS-PAGE, and transferred to a polyvinylidene fluoride membrane or Immobilon-P 1 (Millipore Co., Bedford, MA).…”

Section: Immunoblottingmentioning

confidence: 99%

Obesity-induced increase of CYP2E1 activity and its effect on disposition kinetics of chlorzoxazone in Zucker rats

Khemawoot

Yokogawa

Shimada

et al. 2007

Biochemical Pharmacology

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“…We have reported that the blood concentrations of cyclosporin A [17] and tacrolimus [18] were decreased by combined steroid hormones due to induction of P-gp and/or CYP3A in the liver and small intestine. Hsiu et al [19] also suggested that quercetin significantly decreased the oral bioavailability of cyclosporin A by inducing P-gp and/or CYP3A4.…”

Section: U N C O R R E C T E D P R O O Fmentioning

confidence: 99%

Site-dependent contributions of P-glycoprotein and CYP3A to cyclosporin A absorption, and effect of dexamethasone in small intestine of mice

Jin

Shimada

Yokogawa

et al. 2006

Biochemical Pharmacology

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Modulation of mdr1a and CYP3A gene expression in the intestine and liver as possible cause of changes in the cyclosporin A disposition kinetics by dexamethasone

Cited by 45 publications

References 32 publications

Mechanism of decrease of oral bioavailability of cyclosporin A during immunotherapy upon coadministration of amphotericin B

Mechanism of decrease of oral bioavailability of cyclosporin A during immunotherapy upon coadministration of amphotericin B

Obesity-induced increase of CYP2E1 activity and its effect on disposition kinetics of chlorzoxazone in Zucker rats

Site-dependent contributions of P-glycoprotein and CYP3A to cyclosporin A absorption, and effect of dexamethasone in small intestine of mice

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