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Title: Pharmacokinetics of ruboxistaurin are significantly altered by rifampicin-mediated CYP3A4 induction
Authors: Yeo, K.P. 
Lowe, S.L. 
Lim, M.T.
Voelker, J.R.
Burkey, J.L.
Wise, S.D.
Keywords: 6β-hydroxycortisol
Enzyme induction
Protein kinase C β
Issue Date: Feb-2006
Citation: Yeo, K.P., Lowe, S.L., Lim, M.T., Voelker, J.R., Burkey, J.L., Wise, S.D. (2006-02). Pharmacokinetics of ruboxistaurin are significantly altered by rifampicin-mediated CYP3A4 induction. British Journal of Clinical Pharmacology 61 (2) : 200-210. ScholarBank@NUS Repository.
Abstract: Aims: The aim of this study was to evaluate the effect of rifampicin co-administration on the pharmacokinetics of ruboxistaurin and its active metabolite, N-desmethyl ruboxistaurin and, in addition, to compare the changes in pharmacokinetics of ruboxistaurin and N-desmethyl ruboxistaurin with the urinary 6β-hydroxycortisol:cortisol ratio. Ruboxistaurin is a specific protein-kinase-C β inhibitor in clinical development for the treatment of diabetic microvascular complications. Methods: This was a two-period, one-sequence study. Sixteen healthy male subjects completed both study periods. In period one, a single 64 mg oral dose of ruboxistaurin was administered. In period two, 600 mg rifampicin was administered daily for 9 days, during which another single 64 mg ruboxistaurin dose was administered on day 7. Blood samples were collected and assayed for ruboxistaurin and N-desmethyl ruboxistaurin. CYP3A4 induction was assessed by ratios of urinary 6β-hydroxycortisol: cortisol (6β-OHC:C) obtained via 24 h and morning-spot sampling techniques. Results: Following repeated doses of rifampicin, both the mean Cmax and AUC(0,∞) of ruboxistaurin were significantly reduced by approximately 95% (P ≤ 0.001). For the metabolite, the mean Cmax decreased by 68% (P ≤ 0.001), and AUC(0,∞) decreased by 77% (P ≤ 0.001). The tmax values did not appear affected. The 6β-OHC:C ratios from both 24 h and morning spot methods increased significantly, consistent with CYP3A4 induction. Conclusions: The effect of rifampicin co-administration on the exposure of ruboxistaurin is consistent with ruboxistaurin being a substrate of CYP3A4. Therefore, co-administration with known CYP3A4 inducing agents (rifampicin, carbamazepine, phenobarbital, etc.) may decrease the concentrations of ruboxistaurin and N-desmethyl-ruboxistaurin. In this study, 6β OHC:C ratios substantially underestimated the impact of rifampicin on ruboxistaurin. © 2005 Blackwell Publishing Ltd.
Source Title: British Journal of Clinical Pharmacology
ISSN: 03065251
DOI: 10.1111/j.1365-2125.2005.02540.x
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