Inhibitory effects of sulfonylureas and non‐steroidal anti‐inflammatory drugs on in vitro metabolism of canagliflozin in human liver microsomes

Inhibitory effects of sulfonylureas and non‐steroidal anti‐inflammatory drugs on in vitro... Canagliflozin, used to treat type 2 diabetes mellitus (T2DM), is commonly co‐administered with sulfonylureas. The objective of the present study was to evaluate the possible inhibitory effect of sulfonylureas and non‐steroidal anti‐inflammatory drugs (NSAIDs) on canagliflozin metabolism in vitro. Three sulfonylurea derivatives were evaluated as inhibitors: chlorpropamide, glimepiride and gliclazide. Two other NSAIDs were used as positive control inhibitors: niflumic acid and diclofenac. The rate of formation of canagliflozin metabolites was determined by HPLC analysis of in vitro incubations of canagliflozin as a substrate with and without inhibitors, using human liver microsomes (HLMs). Among sulfonylureas, glimepiride showed the most potent inhibitory effect against canagliflozin M7 metabolite formation, with an IC50 value of 88 μm, compared to chlorpropamide and gliclazide with IC50 values of more than 500 μm. Diclofenac inhibited M5 metabolite formation more than M7, with IC50 values of 32 μm for M5 and 80 μm for M7. Niflumic acid showed no inhibition activity against M5 formation, but had relatively selective inhibitory potency against M7 formation, which is catalysed by UGT1A9, with an IC50 value of 1.9 μm and an inhibition constant value of 0.8 μm. A clinical pharmacokinetic interaction between canagliflozin and sulfonylureas is unlikely. However, a possible clinically important drug interaction between niflumic acid and canagliflozin has been identified. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Biopharmaceutics and Drug Disposition Wiley

Inhibitory effects of sulfonylureas and non‐steroidal anti‐inflammatory drugs on in vitro metabolism of canagliflozin in human liver microsomes

Loading next page...
 
/lp/wiley/inhibitory-effects-of-sulfonylureas-and-non-steroidal-anti-019yCfZDon
Publisher
Wiley Subscription Services, Inc., A Wiley Company
Copyright
Copyright © 2018 John Wiley & Sons, Ltd.
ISSN
0142-2782
eISSN
1099-081X
D.O.I.
10.1002/bdd.2120
Publisher site
See Article on Publisher Site

Abstract

Canagliflozin, used to treat type 2 diabetes mellitus (T2DM), is commonly co‐administered with sulfonylureas. The objective of the present study was to evaluate the possible inhibitory effect of sulfonylureas and non‐steroidal anti‐inflammatory drugs (NSAIDs) on canagliflozin metabolism in vitro. Three sulfonylurea derivatives were evaluated as inhibitors: chlorpropamide, glimepiride and gliclazide. Two other NSAIDs were used as positive control inhibitors: niflumic acid and diclofenac. The rate of formation of canagliflozin metabolites was determined by HPLC analysis of in vitro incubations of canagliflozin as a substrate with and without inhibitors, using human liver microsomes (HLMs). Among sulfonylureas, glimepiride showed the most potent inhibitory effect against canagliflozin M7 metabolite formation, with an IC50 value of 88 μm, compared to chlorpropamide and gliclazide with IC50 values of more than 500 μm. Diclofenac inhibited M5 metabolite formation more than M7, with IC50 values of 32 μm for M5 and 80 μm for M7. Niflumic acid showed no inhibition activity against M5 formation, but had relatively selective inhibitory potency against M7 formation, which is catalysed by UGT1A9, with an IC50 value of 1.9 μm and an inhibition constant value of 0.8 μm. A clinical pharmacokinetic interaction between canagliflozin and sulfonylureas is unlikely. However, a possible clinically important drug interaction between niflumic acid and canagliflozin has been identified.

Journal

Biopharmaceutics and Drug DispositionWiley

Published: Jan 1, 2018

Keywords: ; ; ; ;

References

You’re reading a free preview. Subscribe to read the entire article.


DeepDyve is your
personal research library

It’s your single place to instantly
discover and read the research
that matters to you.

Enjoy affordable access to
over 12 million articles from more than
10,000 peer-reviewed journals.

All for just $49/month

Explore the DeepDyve Library

Unlimited reading

Read as many articles as you need. Full articles with original layout, charts and figures. Read online, from anywhere.

Stay up to date

Keep up with your field with Personalized Recommendations and Follow Journals to get automatic updates.

Organize your research

It’s easy to organize your research with our built-in tools.

Your journals are on DeepDyve

Read from thousands of the leading scholarly journals from SpringerNature, Elsevier, Wiley-Blackwell, Oxford University Press and more.

All the latest content is available, no embargo periods.

See the journals in your area

DeepDyve Freelancer

DeepDyve Pro

Price
FREE
$49/month

$360/year
Save searches from
Google Scholar,
PubMed
Create lists to
organize your research
Export lists, citations
Read DeepDyve articles
Abstract access only
Unlimited access to over
18 million full-text articles
Print
20 pages/month
PDF Discount
20% off