Contribution of Itraconazole Metabolites to Inhibition of CYP3A4 In Vivo

Templeton, Ian E.; Thummel, Kenneth E.; Kharasch, Evan D.; Kunze, Kent L.; Hoffer, Christine; Nelson, Wendel L.; Isoherranen, Nina

doi:10.1038/sj.clpt.6100230

Cited by 113 publications

(127 citation statements)

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“…Dose-dependent pharmacokinetics of ITZ have been described in both rats (Yoo et al, 2000;Shin et al, 2004) and humans (Heykants et al, 1989;Templeton et al, 2008). The concentration-and timedependent clearance and bioavailability of ITZ has been attributed to the inhibition of CYP3A by ITZ and the metabolites that are sequentially formed by CYP3A (Isoherranen et al, 2004;Templeton et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

“…The concentration-and timedependent clearance and bioavailability of ITZ has been attributed to the inhibition of CYP3A by ITZ and the metabolites that are sequentially formed by CYP3A (Isoherranen et al, 2004;Templeton et al, 2008). Typically, the bioavailability of a drug is calculated from the ratio of the total AUC, from zero to infinity, following oral administration to the total AUC, following intravenous administration corrected for any differences in dose.…”

Section: Discussionmentioning

confidence: 99%

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Hydroxyitraconazole, Formed During Intestinal First-Pass Metabolism of Itraconazole, Controls the Time Course of Hepatic CYP3A Inhibition and the Bioavailability of Itraconazole in Rats

et al. 2008

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ABSTRACT:Itraconazole ( During drug discovery and preclinical drug development, in vivo drug disposition and bioavailability studies are often conducted in rats, dogs, primates, and other species. It is increasingly recognized that the fraction of an orally administered drug that reaches the systemic circulation is controlled by both intestinal and hepatic metabolism. However, the contribution of the intestinal epithelia to the overall "first-pass effect" of drugs is difficult to quantify because the small intestine and liver are connected in series. Correct assessment of the separate roles of hepatic and intestinal drug metabolizing capacity in determining drug bioavailability and the extent of first-pass metabolism led us to develop (Uhing and Kimura, 1995a,b;Beno et al., 2001) and validate (Esguerra et al., 2000;Shaw et al., 2002;Uhing et al., 2004) a 5-catheter rat model for pharmacokinetic and drug-drug interaction studies in rats. Drug disposition studies can be conducted in awake, free-moving animals that have fully recovered from surgery and anesthesia and have regained their preoperative weight. Simultaneous sampling allows us to quantify the precise time course of changes in such pharmacokinetic parameters as clearance and hepatic extraction ratio.Itraconazole (ITZ), an orally active triazole antifungal agent, exhibits dose-dependent first-pass metabolism and nonlinear pharmacokinetics in both humans and rats (Hardin et al., 1988;Heykants et al., 1989;Yoo et al., 2000;Shin et al., 2004). Hydroxyitraconazole (OH-ITZ) is a major metabolite that is formed by CYP3A and has antifungal activity similar to ITZ (Heykants et al., 1989;Poirier and Cheymol, 1998). Both ITZ and OH-ITZ are potent inhibitors of CYP3A, and OH-ITZ often displays higher plasma concentrations after ITZ administration (Heykants et al., 1989;Poirier and Cheymol, 1998). Calculation of oral bioavailability compares the time-averaged AUC following oral administration to the time-averaged AUC after intravenous drug administration. Measurement of dose dependence and time-dependence in bioavailability and first-pass metabolism of itraconazole may be unreliable when based upon time-average values for AUC. Using our novel 5-catheter chronic rat model (Fig. 1), we administered ITZ intraduodenally and obtained blood samples simultaneously from aorta, portal vein, and hepatic vein. In particular, this recently validated model (Beno et al., 2001;Uhing et al., 2004) obviated the need to administer ITZ by both the intravenous and

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Hydroxyitraconazole, Formed During Intestinal First-Pass Metabolism of Itraconazole, Controls the Time Course of Hepatic CYP3A Inhibition and the Bioavailability of Itraconazole in Rats

et al. 2008

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“…b Plasma unbound fraction of inhibitors (Templeton et al, 2008, Prueksaritanont et al, 2014, Prueksaritanont et al, 2017 and Goodman & Gilman 10th Edition, 2001. c Concentrations required to inhibit OATP1B-mediated transport by 50% using statins and estradiol 17β glucuronide (Yoshida et al, 2012, Shen et al, 2013, Nakakariya et al, 2016, Vermeer et al, 2016.…”

Section: Discussionmentioning

confidence: 99%

Further Studies to Support the Use of Coproporphyrin I and III as Novel Clinical Biomarkers for Evaluating the Potential for Organic Anion Transporting Polypeptide 1B1 and OATP1B3 Inhibition

et al. 2018

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“…pharmacokinetics）of the inhibitor and of potential active metabolites 14) . Moreover, in the case of mechanism-based inhibition gradual inactivation of the target enzyme by the inhibitor may occur.…”

mentioning

confidence: 99%

Variability of Pharmacokinetic Drug-drug Interactions and Its Consequences

Haefeli

2009

Jpn. J. Clin. Pharmacol. Ther.

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Contribution of Itraconazole Metabolites to Inhibition of CYP3A4 In Vivo

Cited by 113 publications

References 29 publications

Hydroxyitraconazole, Formed During Intestinal First-Pass Metabolism of Itraconazole, Controls the Time Course of Hepatic CYP3A Inhibition and the Bioavailability of Itraconazole in Rats

Hydroxyitraconazole, Formed During Intestinal First-Pass Metabolism of Itraconazole, Controls the Time Course of Hepatic CYP3A Inhibition and the Bioavailability of Itraconazole in Rats

Further Studies to Support the Use of Coproporphyrin I and III as Novel Clinical Biomarkers for Evaluating the Potential for Organic Anion Transporting Polypeptide 1B1 and OATP1B3 Inhibition

Variability of Pharmacokinetic Drug-drug Interactions and Its Consequences

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