In Vivo Effects of Cyclosporin A and Ketoconazole on the Pharmacokinetics of Representative Substrates for P-Glycoprotein and Cytochrome P450 (CYP) 3A in Rats

Kageyama, Michiharu; Namiki, Hitomi; Fukushima, Harumi; Ito, Yoshiaki; Shibata, Nobuhito; Takada, Kanji

doi:10.1248/bpb.28.316

Cited by 57 publications

(34 citation statements)

References 20 publications

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“…Simultaneously, blood samples (210 µL) were obtained by orbital bleeding at 0 (control), 4, 8, 12, 30, 60, 90, 120, 240, 360, and 480 min after intravenous administration, and 0 (control), 5, 10, 20, 30, 60, 90, 120, 240, 360, and 480 min after intragastric administration. Blood samples were centrifuged and plasma samples (100 µL) were stored at -20 °C until use for the liquid chromatography-tandem mass spectrometric (LC-MS) analysis of atorvastatin [14,15] . LC-MS analysis of atorvastatin Concentrations of atorvastatin in the samples were determined using an electrospray ionization LC-MS (Shimadzu, Kyoto, Japan).…”

Section: Methodsmentioning

confidence: 99%

Effects of cyclosporin A and itraconazole on the pharmacokinetics of atorvastatin in rats¹

Dong

Xue

Wang

et al. 2008

Acta Pharmacologica Sinica

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Aim: To evaluate the effects of cyclosporin A and itraconazole, which were used as inhibitors of P-glycoprotein (P-gp) and/or cytochrome P450 (CYP) 3A4 on the pharmacokinetics of atorvastatin in rats. Methods: The pharmacokinetic parameters of atorvastatin were measured after intravenous (2 mg/kg) and intragastric (10 mg/kg) administration of atorvastatin in rats, which were pretreated with cyclosporin A (5, 10, and 20 mg/kg) or itraconazole (5, 10, and 20 mg/kg). Results: Compared with the control rats, cyclosporin A and itraconazole altered the pharmacokinetics of atorvastatin significantly. The AUC 0-t values of atorvastatin after intragastric administration, pretreated with cyclosporin A (5-20 mg/kg), increased by 32.3%, 61.8%, and 187.2%, respectively, but the CL bile values decreased (P<0.01, 5-20 mg/kg). With pretreatment of itraconazole (5-20 mg/kg), the AUC 0-t values of atorvastatin increased by 88.2%, 102%, and 123%, respectively, but the CL bile values decreased (P<0.01, 5-20 mg/kg). Conclusion: These data indicated that cyclosporin A could be effective in inhibiting the efflux of atorvastatin, and itraconazole could be effective in inhibiting both the metabolism and biliary excretion of atorvastatin.

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Section: Methodsmentioning

confidence: 99%

Effects of cyclosporin A and itraconazole on the pharmacokinetics of atorvastatin in rats¹

Dong

Xue

Wang

et al. 2008

Acta Pharmacologica Sinica

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“…or DEX (80 mg/kg, i.p., for 3 days) was chosen as to evoke drug interactions mediated by CYP3A in small animals. [33][34][35][36][37][38] Changes in ∆ 13 CO 2 were thus considered to reflect the alterations of the CYP3A activity caused by KCZ and DEX, that is, less 13 CO 2 production in the case of KCZ-associated CYP3A inhibition and pronounced 13 CO 2 production in the case of DEX-associated CYP3A induction. With regard to the effect of KCZ on the breath response, C max and AUC 0-t with the oral route were remarkably lower than those with the intravenous route (Fig.…”

Section: Discussionmentioning

confidence: 99%

The Use of 13C–Erythromycin as an in vivo Probe to Evaluate CYP3A-mediated Drug Interactions in Rats

Sugiyama

Kikuchi

Inada

et al. 2011

Journal of Pharmaceutical Sciences

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“…While KTZ is a recognised CYP 450 inhibitor (Newton et al 1995;Pelkonen et al 2008), it is also regarded as an inhibitor of Pgp-linked drug efflux pumps (Siegsmund et al 1994;Zhang et al 1998;Kim et al 1999;Wang et al 2002;Ward et al 2004;Kageyama et al 2005). Over-expression of Pgp has been linked to the development of resistance against a number of anthelmintics (Xu et al 1998;Molento and Prichard 1999;Kerboeuf et al 2003;Wolstenholme et al 2004;Prichard and Roulet 2007;Messerli et al 2009).…”

Section: Discussionmentioning

confidence: 99%

Erratum to: Inhibition of triclabendazole metabolism in vitro by ketoconazole increases disruption to the tegument of a triclabendazole-resistant isolate of Fasciola hepatica

et al. 2011

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A study has been carried out to investigate whether the action of triclabendazole (TCBZ) against Fasciola hepatica is altered by inhibition of drug metabolism. The cytochrome P450 (CYP 450) enzyme pathway was inhibited using ketoconazole (KTZ) to see whether a TCBZ-resistant isolate could be made more sensitive to TCBZ action. The Oberon TCBZ-resistant and Cullompton TCBZ-susceptible isolates were used for these experiments. The CYP 450 system was inhibited by a 2-h pre-incubation in ketoconazole (40 μM), then incubated for a further 22 h in NCTC medium containing either KTZ, KTZ+nicotinamide adenine dinucleotide phosphate (NADPH) (1 nM), KTZ+NADPH+ TCBZ (15 μg/ml), or KTZ+NADPH+triclabendazole sulphoxide (TCBZ.SO; 15 μg/ml). Changes to fluke ultrastructure following drug treatment and metabolic inhibition were assessed using transmission electron microscopy. After treatment with either TCBZ or TCBZ.SO on their own, there was greater disruption to the TCBZ-susceptible than TCBZ-resistant isolate. However, co-incubation with KTZ+ TCBZ, but more particularly KTZ+TCBZ.SO, led to more severe changes to the TCBZ-resistant isolate than with each drug on its own: for example, there was severe swelling of the basal infolds and their associated mucopolysaccharide masses, accompanied by an accumulation of secretory bodies just below the apex. Golgi complexes were greatly reduced or absent in the tegumental cells and the synthesis, production, and transport of secretory bodies were badly disrupted. With the TCBZ-susceptible Cullompton isolate, there was limited potentiation of drug action. The results support the concept of altered drug metabolism in TCBZresistant flukes and this process may play a role in the development of drug resistance.

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In Vivo Effects of Cyclosporin A and Ketoconazole on the Pharmacokinetics of Representative Substrates for P-Glycoprotein and Cytochrome P450 (CYP) 3A in Rats

Cited by 57 publications

References 20 publications

Effects of cyclosporin A and itraconazole on the pharmacokinetics of atorvastatin in rats¹

Effects of cyclosporin A and itraconazole on the pharmacokinetics of atorvastatin in rats¹

The Use of 13C–Erythromycin as an in vivo Probe to Evaluate CYP3A-mediated Drug Interactions in Rats

Erratum to: Inhibition of triclabendazole metabolism in vitro by ketoconazole increases disruption to the tegument of a triclabendazole-resistant isolate of Fasciola hepatica

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In Vivo Effects of Cyclosporin A and Ketoconazole on the Pharmacokinetics of Representative Substrates for P-Glycoprotein and Cytochrome P450 (CYP) 3A in Rats

Cited by 57 publications

References 20 publications

Effects of cyclosporin A and itraconazole on the pharmacokinetics of atorvastatin in rats1

Effects of cyclosporin A and itraconazole on the pharmacokinetics of atorvastatin in rats1

The Use of 13C–Erythromycin as an in vivo Probe to Evaluate CYP3A-mediated Drug Interactions in Rats

Erratum to: Inhibition of triclabendazole metabolism in vitro by ketoconazole increases disruption to the tegument of a triclabendazole-resistant isolate of Fasciola hepatica

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Effects of cyclosporin A and itraconazole on the pharmacokinetics of atorvastatin in rats¹

Effects of cyclosporin A and itraconazole on the pharmacokinetics of atorvastatin in rats¹