Abstract
Itraconazole is a fungistatic agent that, although highly lipophilic, shows poor transport through the blood brain barrier that may be due to efflux proteins. The combined administration of an efflux inhibitor with itraconazole should increase cerebral itraconazole concentrations and therefore, improve the treatment ofCryptococcus neoformans meningitis with this antifungal agent. To test this hypothesis, we have studied the influence of murine cerebral infection with C. neoformans and the inhibition of efflux by intraperitoneal injection of a P-glycoprotein inhibitor, GF120918 [N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)-ethyl]-phenyl)9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide], on the pharmacokinetics of itraconazole in plasma and brain after a single intraperitoneal itraconazole injection. We also investigated the influence of efflux inhibition on the efficacy of repeated doses of itraconazole in this murine model. The results showed that in healthy and infected mice pretreated or not with GF120918, plasma itraconazole values of area under the curve (AUC) were similar. In contrast, cerebral values of AUC were higher in infected mice compared with healthy mice. Moreover, the pretreatment of infected mice with GF120918 significantly increased cerebral itraconazole values of area under the curve and decreased weight loss in the treatment with itraconazole of a cerebral infection with C. neoformans.
Footnotes
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This work was supported by a grant from Janssen Cilag.
- Abbreviations used are::
- AIDS
- acquired immunodeficiency syndrome
- ITC
- itraconazole
- P-gp
- P-glycoprotein
- mdr
- multidrug resistance
- MRP
- multidrug resistance proteins
- BCRP
- breast cancer resistance protein
- PSC833
- valspodar
- HIV
- human immunodeficiency virus
- HPLC
- high performance liquid chromatography
- R51012
- cis-4-(4-[4-[4-{[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3,dioxolan-4-yl]-methoxy] phenyl}-1-piperazinyl]phenyl)-2,4-dihydro-5-methyl-2-(3-methylbutyl)-3H-1,2,4-triazol-3-one
- Tmax
- time to maximal concentration
- AUC
- area under the curve
- λZ
- apparent terminal elimination rate constant
- Cl
- plasma clearance
- F
- bioavailability
- VZ
- plasma volume of distribution
- BBB
- blood brain barrier
- GF120918
- N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)-ethyl]-phenyl)9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide
- LY336979
- zosuquidar
- Received July 5, 2002.
- Accepted December 4, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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