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Effects of Antibacterial Drugs on Lansoprazole Metabolism in Vitro and in Vivo

Author: XiangDaoChun
Tutor: LiuDong
School: Huazhong University of Science and Technology
Course: Pharmacy
Keywords: cytochrome P450 enzymes lansoprazole 5-hydroxylansoprazole lansoprazole sulfone HPLC-MS/MS pharmacokinetics metabolism
CLC: R96
Type: Master's thesis
Year: 2011
Downloads: 48
Quote: 0
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Abstract


Background: Lansoprazole is a proton pump inhibitor that inactivates the H+/K+-ATPase pump in parietal cells. Lansoprazole can extensively be metabolized by cytochrome 2C19 and cytochrome 3A4 in the liver, and the metabolites were 5-hydroxylansoprazole and lansoprazole sulfone respectively. Since 90% peptic ulcer are accompanied with helicobacter pylori infection, and the antibiotics amoxicillin, clarithromycin, metronidazole and furazolidone are very effective antibacterial especially for Hp, so using lansoprazole accompanied with one of these antibiotics is very usual.Objective: to evaluate the effect of amoxicillin, clarithromycin, metronidazole and furazolidone on the metabolism of lasoprazole in rats in vivo and vitro respectively.Methods: Forty-two rats were randomLy divided into seven groups, lansoprazole(8mg·kg-1)+ 0.9%saline solution, lansoprazole(8mg·kg-1)+ Ketoconazole(5mg·kg-1), lansoprazole (8mg·kg-1) + Tranylcypromine(5mg·kg-1), lansoprazole(8mg·kg-1)+ amoxicillin (100mg·kg-1), lansoprazole(8mg·kg-1) Clarithromycin(8mg·kg-1), lansoprazole(8mg·kg-1)+ metronidazole (200mg·kg-1), lansoprazole(8mg·kg-1)+ furazolidone (40mg·kg-1). Plasma concentrations of lansoprazole and its metabolite 5-hydroxylansoprazole and lansoprazole sulfone were determined by LC-MS/MS. Pharmacokinetical parameters of these three matters were calculated.Based on the data, 3 antibiotics were selected to study the effects on CYP2C19/CYP3A4 in liver microsomes systems, and calculate the inhibitory potency and evaluate the mechanism of some antibiotics on CYP2C19/CYP3A4.Results: the pharmacokinetic parameters showed that clarithroycin, furazolidone significantly increased AUC of lansoprazole from （487.34±290.80） ng/L·h to （854.85±295.18） ng/L·h （P<0.05） and （779.82±310.2） respectively, at the same time, they both decreased the AUC of lansoprazole sulfone, and have no significant effect to the AUC of 5-hydroxylansoprazole. Metronidazole dramatically decreased the AUC of lansprazole, and there is no effect on the pharmacokinetics with the use of amoxicillin.In the in vitro study, the results showed that clarithromycin, furazolidone could inhibit the activity of CYP3A4, and the IC50 values were 66μM and 55μM respectively. In addition, furazolidone inhibit the activity of CYP2C19, and the IC50 value is 46μM. All antibiotcs inhibit lansoprazole biotransformation via cytochrome by apparently mixed type mechanism.Conclusion: In vivo, clarithromycin and furazolidone mainly affected the metabolism of lansoprazole by inhibiting the formation of lansoprazole sulfone. By this way, the two kinds of antibiotics decrease the clearance of lansprazole, and thereby affecting the bioavailability in rats. Metronidazole could not affected the the biotransformation effectively. The disposition of lansoprazole in rat is not affected by amoxicillin.

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