Effect of itraconazole on the pharmacokinetics of digoxin in guinea pigs

Nishihara, Kenji; Hibino, Junko; Kotaki, Hajime; Sawada, Yasufumi; Iga, Tatsuji

doi:10.1002/(sici)1099-081x(199904)20:3<145::aid-bdd167>3.0.co;2-h

Cited by 18 publications

(5 citation statements)

References 21 publications

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“…Digoxin is a substrate of P-glycoprotein, leading to the elimination of digoxin from enterocytes through the intestinal mucosa into the gut lumen [2][3][4] and by kidney tubular cells into urine. [5][6][7] Increases in serum digoxin levels by several drugs, such as quinidine, [8][9][10][11] verapamil, 12,13 cyclosporine, 14,15 itraconazole, 16,17 talinolol, 18 and macrolide antibiotics, 19 have been attributed to the inhibition of P-glycoprotein.…”

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confidence: 99%

The Effect of Erythromycin and Clarithromycin on the Pharmacokinetics of Intravenous Digoxin in Healthy Volunteers

Tsutsumi¹,

Kotegawa²,

Kuranari³

et al. 2002

Journal of Clinical Pharmacology

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Several case reports have suggested an interaction between digoxin and macrolide antibiotics. The authors investigated the effect of erythromycin and clarithromycin on the pharmacokinetics of intravenously administered digoxin (0.5 mg) in healthy subjects. Nine male subjects participated in three studies (digoxin alone, digoxin with erythromycin, and digoxin with clarithromycin). Subjects took erythromycin (800 mg per day) or clarithromycin (400 mg per day) on the day before digoxin dosing and during the kinetic study, Neither of the macrolides affected serum digoxin concentration-time curves. However, more than 1.3-fold increases in urinary digoxin excretions were observed during erythromycin and clarithromycin coadministration compared with digoxin alone. There were significant differences in renal clearance between macrolide coadministration and the control condition (digoxin alone: 98.4 ml/min; digoxin with erythromycin: 137.3 ml/min; digoxin with clarithromycin: 133.6 ml/min). In conclusion, neither erythromycin nor clarithromycin has a significant effect on serum digoxin disposition after an intravenous administration. Renal digoxin excretion is not inhibited but rather enhanced by both macrolides.

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confidence: 99%

The Effect of Erythromycin and Clarithromycin on the Pharmacokinetics of Intravenous Digoxin in Healthy Volunteers

Tsutsumi¹,

Kotegawa²,

Kuranari³

et al. 2002

Journal of Clinical Pharmacology

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“…Moreover, the coadministration of ITZ and digoxin (DGX), a cardiac glycoside, caused nausea, vomiting, and visual disturbances (19). To clarify the mechanism of interaction of ITZ and DGX, we investigated the effect of ITZ on the pharmacokinetic behavior of DGX in guinea pigs (20). We found a reduction in metabolic, biliary, and urinary clearances of DGX after coadministration of ITZ in guinea pigs.…”

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confidence: 99%

P-Glycoprotein-Mediated Transport of Itraconazole across the Blood-Brain Barrier

Miyama

Takanaga

Matsuo

et al. 1998

Antimicrob Agents Chemother

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The mechanism for the accumulation of itraconazole (ITZ) in its elimination from the brain was studied in rats and mice. The concentration of ITZ in liver tissue declined in parallel with the plasma ITZ concentration until 24 h after intravenous injection of the drug (half-life, 5 h); however, the ITZ in brain tissue rapidly disappeared (half-life, 0.4 h). The time profiles of the brain/plasma ITZ concentration ratio (Kp value) showed a marked overshooting, and the Kp value increased with increasing dose; these phenomena were not observed in the liver tissue. This finding indicates the occurrence of a nonlinear efflux of ITZ from the brain to the blood. Moreover, based on a pharmacokinetic model which hypothesized processes for both nonlinear and linear effluxes of ITZ from the brain to the blood, we found that the efflux rate constant in the saturable process was approximately sevenfold larger than that in the nonsaturable process. TheKp value for the brain tissue was significantly increased in the presence of ketoconazole or verapamil. The brainKp value for mdr1a knockout mice was also significantly increased compared with that of control mice. Moreover, the uptake of vincristine or vinblastine, both of which are substrates of the P glycoprotein (P-gp), into mouse brain capillary endothelial cells was also significantly increased by ITZ or verapamil. In conclusion, P-gp in the brain capillary endothelial cells participates in a process of active efflux of ITZ from the brain to the blood at the blood-brain barrier, and ITZ can be an inhibitor of various substrates of P-gp.

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“…The findings suggest that ketoconazole is a modest inhibitor of P-gp (and possibly other transporters) in addition to its well documented ability to inhibit CYP3A in humans with high potency (Venkatakrishnan et al, 2000). P-gp inhibition is also a property of the structurally similar azole antifungal agent, itraconazole (Miyama et al, 1998;Nishihara et al, 1999;Takara et al, 2000;Wang et al, 2002). However, it remains unclear whether ketoconazole itself is a substrate for transport by P-gp.…”

Section: Discussionmentioning

confidence: 99%

Interaction of Triazolam and Ketoconazole in P-Glycoprotein-Deficient Mice

Moltke

Granda²,

Grassi³

et al. 2004

Drug Metab Dispos

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ABSTRACT:The role of P-glycoprotein (P-gp) on the distribution of the benzodiazepine triazolam (TRZ) and the azole antifungal agent ketoconazole (KET), and on the TRZ-KET interaction, was studied using mdr1a(؊) or mdr1a/b(؊/؊) mice (P-gp-deficient mice) and matched controls. TRZ and KET also were studied in Caco-2 cells in Transwell culture. After single i.p. injections of TRZ or KET in separate groups of control mice, brain concentrations of TRZ exceeded those in serum [brain/serum area under the concentration curve (AUC) ratio, 5.0], whereas brain/serum AUC ratios for KET were approximately 0.5. On the basis of single time points, brain concentrations of TRZ, or brain/serum ratios, were similar in P-gp-deficient animals compared with controls, whereas P-gpdeficient animals had significantly higher KET brain concentrations and brain/serum ratios. Coadministration of KET with TRZ increased TRZ concentrations in serum, liver, and brain, both in controls and in P-gp-deficient animals, probably attributable to impairment by KET of CYP3A-mediated clearance of TRZ. However, KET did not increase brain/serum ratios of TRZ in either group. In Caco-2 cells, basal-to-apical flux of TRZ was higher than apical-to-basal flux. However, verapamil (100 M) did not alter flux in either direction. KET inhibited basal-to-apical transport of rhodamine-123, with a 50% inhibitory concentration of 2.7 M. Thus, TRZ does not appear to undergo measurable blood-brain barrier efflux transport by P-gp in this animal model. KET impairs clearance of TRZ but does not increase tissue uptake. However, KET itself may be a substrate for efflux transport at the blood-brain barrier.

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Effect of itraconazole on the pharmacokinetics of digoxin in guinea pigs

Cited by 18 publications

References 21 publications

The Effect of Erythromycin and Clarithromycin on the Pharmacokinetics of Intravenous Digoxin in Healthy Volunteers

The Effect of Erythromycin and Clarithromycin on the Pharmacokinetics of Intravenous Digoxin in Healthy Volunteers

P-Glycoprotein-Mediated Transport of Itraconazole across the Blood-Brain Barrier

Interaction of Triazolam and Ketoconazole in P-Glycoprotein-Deficient Mice

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