Inhibitory Effects of Sulfonylureas and Non-Steroidal Anti-Inflammatory Drugs on In-Vitro Metabolism of Canagliflozin in Human Liver Microsomes
Algeelani, Sara.
2017
-
Abstract:
Canagliflozin, a sodium-glucose transport protein 2 (SGLT2) inhibitor, is a novel drug
used to treat type 2 diabetes mellitus (T2DM). A phase II glucuronide conjugation
reaction is the primary elimination pathway of canagliflozin. Uridine diphosphate
glucuronosyltransferases (UGTs) are the responsible enzymes for the glucuronidation
reactions that occur in phase II metabolism. The ... read moreglucuronidation of canagliflozin
results in formation of two major inactive metabolites, M7 and M5 that are catalyzed by
UGT1A9 and UGT2B4, respectively. Canagliflozin is commonly co-administered with other
antidiabetic agents such as sulfonylureas. Until now, there is no documented in vitro
drug-drug interactions (DDIs) study conducted to assess the inhibitory effect of other
drugs on the metabolism of canagliflozin. Moreover, the inhibitory effects of
sulfonylureas against UGTs isoenzymes are not well established. In this study, the
inhibitory effect on the metabolism of the two metabolites of canagliflozin, M7, and M5
has been investigated using three sulfonylurea drugs as inhibitors, including
chlorpropamide, glimepiride, and gliclazide. Additionally, two non-steroidal
anti-inflammatory drugs were included as positive controls which are known for their
inhibitory effect against UGT1A9 (niflumic acid) and UGT2B4 (diclofenac). The formation
rate of M7 and M5 metabolites were monitored by HPLC after incubation of canagliflozin
as a substrate with and without inhibitors at different concentrations. The IC50 values
were calculated for all inhibitors by using five different individual human liver
microsomes (HLMs) including pooled HLMs. Ki values were calculated for niflumic acid by
using additional three individual HLMs and a pooled sample. Among sulfonylureas,
glimepiride showed the most potent inhibitory effect against M7 metabolite formation
with an IC50 value of 88 ± 4 µM, compared to chlorpropamide and gliclazide
with IC50 values of more than 500µM. Diclofenac inhibited M5 metabolite formation,
which is catalyzed by UGT2B4, more than M7, with IC50 values of 32 ± 13µM for
M5 and 80 ± 13 µM for M7. Niflumic acid showed no inhibition activity against
M5 formation, but showed relatively selective inhibitory potency against M7 formation
with an IC50 value of 1.9 ± 0.03µM and a Ki value of 0.8±0.25 µM.
The results of this study suggest that there may not be a metabolic interaction between
canagliflozin and sulfonylureas. This study also demonstrates a possible clinical
interaction between niflumic acid and canagliflozin. The low Ki value of niflumic acid,
when compared to its maximum plasma therapeutic concentration, suggest the possibility
of a clinical drug interaction which could be of therapeutic
impotence.
Thesis (M.S.)--Tufts University, 2017.
Submitted to the Dept. of Pharmacology & Experimental Therapeutics.
Advisor: David Greenblatt.
Keyword: Pharmacology.read less - ID:
- zw12zh30s
- Component ID:
- tufts:22742
- To Cite:
- TARC Citation Guide EndNote
