Pharmacokinetics of Ketoconazole Administered Intravenously to Dogs and Orally as Tablet and Solution to Humans and Dogs

Baxter, J. G.; Brass, Corstiaan; Schentag, Jerome J.; Slaughter, Richard L.

doi:10.1002/jps.2600750504

Cited by 48 publications

(40 citation statements)

References 18 publications

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“…In the rat, after a 5 mg/kg dose, ketoconazole displays a plasma clearance of 14.4 ml/min/kg, a volume of distribution that approximates total body water, and a half-life of 0.58 h (Remmel et al, 1987). After a 20 mg/kg dose in the dog, clearance is 2.7 ml/min/kg with a volume of distribution that approximates total body water and a half-life of 2.7 h (Baxter et al, 1986). Our data for the disposition of ketoconazole in the cynomolgus monkey are consistent with these observations, although the monkey demonstrates somewhat higher plasma clearance (as a fraction of hepatic plasma flow) than that reported in the rat or dog.…”

Section: Downloaded Fromsupporting

confidence: 83%

Development of an in Vivo Preclinical Screen Model to Estimate Absorption and First-Pass Hepatic Extraction of Xenobiotics. Ii. Use of Ketoconazole to Identify P-Glycoprotein/Cyp3a-Limited Bioavailability in the Monkey

Ward

Stelman²,

Morgan³

et al. 2004

Drug Metab Dispos

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This article is available online at http://dmd.aspetjournals.org ABSTRACT:The effect of P-glycoprotein (Pgp) and/or CYP3A on the disposition of xenobiotics has been extensively investigated and is often of interest during drug discovery lead optimization. We have previously described a monkey pharmacokinetic screen to rapidly estimate absorption and first-pass extraction. In the present work, this monkey screen has been expanded to include an assessment of Pgp/CYP3A effects on absorption and first-pass extraction, using ketoconazole as a prototypic dual Pgp/CYP3A inhibitor. To generate a ketoconazole dosing regimen, the pharmacokinetics of ketoconazole were first determined in the monkey and were found to be consistent with that previously described in the rat, dog, and human. Dose-ranging experiments demonstrated that a single 10-mg/kg intraduodenal ketoconazole dose would provide an appropriate exposure; this dose was used throughout subsequent interaction experiments. Next, erythromycin and propranolol were explored as positive and negative control substrates for Pgp/ CYP3A interactions, respectively. As anticipated, ketoconazole produced no change in the absorption or first-pass extraction of propranolol but resulted in a substantial increase in absorption and decrease in first-pass extraction of erythromycin. Finally, this ketoconazole-based monkey screen was deployed in a drug discovery setting, and examples of such use are presented. These experiments have allowed a more complete characterization of ketoconazole as a prototypic dual Pgp/CYP3A inhibitor and its use as a tool in a preclinical setting and further demonstrate the use of the monkey to investigate the role of Pgp/CYP3A in limiting the oral bioavailability of new drug candidates.

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Section: Downloaded Fromsupporting

confidence: 83%

Development of an in Vivo Preclinical Screen Model to Estimate Absorption and First-Pass Hepatic Extraction of Xenobiotics. Ii. Use of Ketoconazole to Identify P-Glycoprotein/Cyp3a-Limited Bioavailability in the Monkey

Ward

Stelman²,

Morgan³

et al. 2004

Drug Metab Dispos

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“…It is well recognized that combination antifungal therapy has potential synergistic effects (40)(41)(42)(43). Furthermore, the MICs of both drugs were suggestive of drug efficacy, as these concentrations should be readily achieved on the basis of canine pharmacokinetic studies (44,45). Clinical and radiographic improvements observed in the dog in our report substantiated the efficacy of this multimodal therapy.…”

Section: Discussionsupporting

confidence: 64%

Clinical, Morphological, and Molecular Characterization of Penicilliumcanissp. nov., Isolated from a Dog with Osteomyelitis

et al. 2014

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f Infections caused by Penicillium species are rare in dogs, and the prognosis in these cases is poor. An unknown species of Penicillium was isolated from a bone lesion in a young dog with osteomyelitis of the right ilium. Extensive diagnostic evaluation did not reveal evidence of dissemination. Resolution of lameness and clinical stability of disease were achieved with intravenous phospholipid-complexed amphotericin B initially, followed by long-term combination therapy with terbinafine and ketoconazole. A detailed morphological and molecular characterization of the mold was undertaken. Sequence analysis of the internal transcribed spacer revealed the isolate to be closely related to Penicillium menonorum and Penicillium pimiteouiense. Additional sequence analysis of ␤-tubulin, calmodulin, minichromosome maintenance factor, DNA-dependent RNA polymerase, and prerRNA processing protein revealed the isolate to be a novel species; the name Penicillium canis sp. nov. is proposed. Morphologically, smooth, ovoid conidia, a greenish gray colony color, slow growth on all media, and a failure to form ascomata distinguish this species from closely related Penicillium species.

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“…Odds (201) (143). In another study in human volunteers and in mongrel dogs, ketoconazole solution was more readily absorbed and gave higher peak plasma concentrations than a tablet formulation (14). Thus, bioavailability of the solution was greater than that of the tablet.…”

Section: Ketoconazolementioning

confidence: 99%

Overview of medically important antifungal azole derivatives

1988

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Fungal infections are a major burden to the health and welfare of modern humans. They range from simply cosmetic, non-life-threatening skin infections to severe, systemic infections that may lead to significant debilitation or death. The selection of chemotherapeutic agents useful for the treatment of fungal infections is small. In this overview, a major chemical group with antifungal activity, the azole derivatives, is examined. Included are historical and state of the art information on the in vitro activity, experimental in vivo activity, mode of action, pharmacokinetics, clinical studies, and uses and adverse reactions of imidazoles currently marketed (clotrimazole, miconazole, econazole, ketoconazole, bifonazole, butoconazole, croconazole, fenticonazole, isoconazole, oxiconazole, sulconazole, and tioconazole) and under development (aliconazole and omoconazole), as well as triazoles currently marketed (terconazole) and under development (fluconazole, itraconazole, vibunazole, alteconazole, and ICI 195,739).

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Pharmacokinetics of Ketoconazole Administered Intravenously to Dogs and Orally as Tablet and Solution to Humans and Dogs

Cited by 48 publications

References 18 publications

Development of an in Vivo Preclinical Screen Model to Estimate Absorption and First-Pass Hepatic Extraction of Xenobiotics. Ii. Use of Ketoconazole to Identify P-Glycoprotein/Cyp3a-Limited Bioavailability in the Monkey

Development of an in Vivo Preclinical Screen Model to Estimate Absorption and First-Pass Hepatic Extraction of Xenobiotics. Ii. Use of Ketoconazole to Identify P-Glycoprotein/Cyp3a-Limited Bioavailability in the Monkey

Clinical, Morphological, and Molecular Characterization of Penicilliumcanissp. nov., Isolated from a Dog with Osteomyelitis

Overview of medically important antifungal azole derivatives

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