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|Title:||Pharmacokinetics of ruboxistaurin are significantly altered by rifampicin-mediated CYP3A4 induction||Authors:||Yeo, K.P.
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. https://doi.org/10.1111/j.1365-2125.2005.02540.x||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||URI:||http://scholarbank.nus.edu.sg/handle/10635/112011||ISSN:||03065251||DOI:||10.1111/j.1365-2125.2005.02540.x|
|Appears in Collections:||Staff Publications|
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