Development and Validation of an LC-MS/MS Method for Simultaneous Determination of Canagliflozin and Metformin HCl in Rat Plasma and its Application

Author(s): Vivek Nalawade*, Vaibhav A. Dixit, Amisha Vora, Himashu Zade

Journal Name: Current Pharmaceutical Analysis

Volume 16 , Issue 6 , 2020


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Graphical Abstract:


Abstract:

Background: Food and herbal extracts rich in Quercetin (QRT) are often self-medicated by diabetics and can potentially alter the pharmacokinetics (PK) of Metformin HCl (MET) and Canagliflozin (CNG) leading to food or herb-drug interactions and reduced therapeutic efficacy. However, the impact of these flavonoids on the pharmacokinetic behaviour of MET and CNG is mostly unknown.

Methods: A simple one-step protein precipitation method was developed for the determination of MET and CNG from rat plasma. The mobile phase chosen was MeOH 65% and 35% water containing 0.1% formic acid at a flow rate of 1mL/min.

Results: The retention time of MET, internal standard (Valsartan) and CNG was 1.83, 6.2 and 8.2 min, respectively. The method was found to be linear in the range of 200 - 8000 ng/mL for CNG and 100 = 4000 ng/ml for MET. Precision and accuracy of the method were below 20% at LLOQ and below 15% for LQC, MQC, and HQC.

Conclusion: The method was successfully applied for the determination of PK of MET and CNG by using 100 μL of rat plasma. QRT co-administration affects the PK parameters of MET and CNG. This alteration in PK parameters might be of significant use for clinicians and patients.

Keywords: Pharmacokinetics, validation, quercetin, canagliflozin, metformin HCl, LC-MS/MS.

[1]
Fala, L. Invokamet (Canagliflozin plus Metformin HCl): first fixeddose combination with an SGLT2 inhibitor approved for the treatment of patients with type 2 diabetes. Am. Health Drug Benefits, 2015, 8(Spec Feature), 70-74.
[2]
Davidson, J.A.; Sloan, L. Fixed-dose combination of canagliflozin and metformin for the treatment of type 2 diabetes: an overview. Adv. Ther., 2017, 34(1), 41-59.
[http://dx.doi.org/10.1007/s12325-016-0434-2] [PMID: 27854055]
[3]
Squibb, B-M. Glucophage ® XR Label; Bristol-Myers Squibb Company, 2008, pp. 3-32.
[4]
Chen, X.; Hu, P.; Vaccaro, N.; Polidori, D.; Curtin, C.R.; Stieltjes, H.; Sha, S.; Weiner, S.; Devineni, D. Pharmacokinetics, pharmacodynamics, and safety of single-dose canagliflozin in healthy chinese subjects. Clin. Ther., 2015, 37(7), 1483-1492.e1.
[http://dx.doi.org/10.1016/j.clinthera.2015.04.015] [PMID: 26048186]
[5]
McCreight, L.J.; Bailey, C.J.; Pearson, E.R. Metformin and the gastrointestinal tract. Diabetologia, 2016, 59(3), 426-435.
[http://dx.doi.org/10.1007/s00125-015-3844-9] [PMID: 26780750]
[6]
Garrison, K.L.; Sahin, S.; Benet, L.Z. Few drugs display flip-flop pharmacokinetics and these are primarily associated with classes 3 and 4 of the BDDCS. J. Pharm. Sci., 2015, 104(9), 3229-3235.
[http://dx.doi.org/10.1002/jps.24505] [PMID: 26010239]
[7]
Dujic, T.; Zhou, K.; Donnelly, L.A.; Tavendale, R.; Palmer, C.N.A.; Pearson, E.R. association of organic cation transporter 1 with intolerance to metformin in type 2 diabetes: A GoDARTS Study. Diabetes, 2015, 64(5), 1786-1793.
[http://dx.doi.org/10.2337/db14-1388] [PMID: 25510240]
[8]
Mamidi, R.N.V.S.; Dallas, S.; Sensenhauser, C.; Lim, H.K.; Scheers, E.; Verboven, P.; Cuyckens, F.; Leclercq, L.; Evans, D.C.; Kelley, M.F.; Johnson, M.D.; Snoeys, J. In vitro and physiologically-based pharmacokinetic based assessment of drug-drug interaction potential of canagliflozin. Br. J. Clin. Pharmacol., 2017, 83(5), 1082-1096.
[http://dx.doi.org/10.1111/bcp.13186] [PMID: 27862160]
[9]
Francke, S.; Mamidi, R.N.V.S.; Solanki, B.; Scheers, E.; Jadwin, A.; Favis, R.; Devineni, D. In vitro metabolism of canagliflozin in human liver, kidney, intestine microsomes, and recombinant uridine diphosphate glucuronosyltransferases (UGT) and the effect of genetic variability of UGT enzymes on the pharmacokinetics of canagliflozin in humans. J. Clin. Pharmacol., 2015, 55(9), 1061-1072.
[http://dx.doi.org/10.1002/jcph.506] [PMID: 25827774]
[10]
US prescribing information. Invokana (Canagliflozin) Tablets, for Oral Use, 2013.
[11]
Pattanawongsa, A.; Chau, N.; Rowland, A.; Miners, J.O. Inhibition of Human UDP-glucuronosyltransferase enzymes by canagliflozin and dapagliflozin: implications for drug-drug interactions. Drug Metab. Dispos., 2015, 43(10), 1468-1476.
[http://dx.doi.org/10.1124/dmd.115.065870] [PMID: 26180128]
[12]
Gupta, R.C.; Chang, D.; Nammi, S.; Bensoussan, A.; Bilinski, K.; Roufogalis, B.D. Interactions between antidiabetic drugs and herbs: an overview of mechanisms of action and clinical implications. Diabetol. Metab. Syndr., 2017, 9(1), 59.
[http://dx.doi.org/10.1186/s13098-017-0254-9] [PMID: 28770011]
[13]
Manya, K.; Champion, B.; Dunning, T. The use of complementary and alternative medicine among people living with diabetes in Sydney. BMC Complement. Altern. Med., 2012, 12(1), 2.
[http://dx.doi.org/10.1186/1472-6882-12-2] [PMID: 22240113]
[14]
Modak, M.; Dixit, P.; Londhe, J.; Ghaskadbi, S.; Devasagayam, T.P.A. Indian herbs and herbal drugs used for the treatment of diabetes. J. Clin. Biochem. Nutr., 2007, 40(3), 163-173.
[http://dx.doi.org/10.3164/jcbn.40.163] [PMID: 18398493]
[15]
Glaeser, H.; Bujok, K.; Schmidt, I.; Fromm, M.F.; Mandery, K. Organic anion transporting polypeptides and organic cation transporter 1 contribute to the cellular uptake of the flavonoid quercetin. Naunyn Schmiedebergs Arch. Pharmacol., 2014, 387(9), 883-891.
[http://dx.doi.org/10.1007/s00210-014-1000-6] [PMID: 24947867]
[16]
Jiang, W.; Ming, H. Mutual interactions between flavonoids and enzymatic and transporter elements responsible for flavonoid disposition via phase ii metabolic pathways wen. RSC Advances, 2013, 31(9), 1713-1723.
[17]
Mamidi, R.N.V.S.; Cuyckens, F.; Chen, J.; Scheers, E.; Kalamaridis, D.; Lin, R.; Silva, J.; Sha, S.; Evans, D.C.; Kelley, M.F.; Devineni, D.; Johnson, M.D.; Lim, H.K. Metabolism and excretion of canagliflozin in mice, rats, dogs, and humans. Drug Metab. Dispos., 2014, 42(5), 903-916.
[http://dx.doi.org/10.1124/dmd.113.056440] [PMID: 24568888]
[18]
Sampson, L.; Rimm, E.; Hollman, P.C.H.; de Vries, J.H.M.; Katan, M.B. Flavonol and flavone intakes in US health professionals. J. Am. Diet. Assoc., 2002, 102(10), 1414-1420.
[http://dx.doi.org/10.1016/S0002-8223(02)90314-7] [PMID: 12396158]
[19]
Suhailah, S.A-J.; Soheir, N.A.E-R. Effect of quercetin nanoparticles on the kidney of the streptozotocin-induced diabetes in male rats: a histological study and serum biochemical alterations. Afr. J. Biotechnol., 2017, 16(39), 1944-1952.
[http://dx.doi.org/10.5897/AJB2017.15999]
[20]
Kotadiya, C.; Patel, U.D.; Modi, C.M.; Patel, H.B.; Kalaria, V.A. Effect of opuntia elatior fruit juice and quercetin administration on glucose level, lipid profile. Hyperalgesic Response and Spontaneous Motor Activity in Diabetic Rats., 2017, 6(8), 150-155.
[21]
Yang, D.K.; Kang, H-S. Anti-diabetic effect of cotreatment with quercetin and resveratrol in streptozotocin-induced diabetic rats. Biomol. Ther. (Seoul), 2018, 26(2), 130-138.
[http://dx.doi.org/10.4062/biomolther.2017.254] [PMID: 29462848]
[22]
Kunasegaran, T.; Mustafa, M.R.; Achike, F.I.; Murugan, D.D. Quercetin and pioglitazone synergistically reverse endothelial dysfunction in isolated aorta from fructose-streptozotocin (F-STZ)-induced diabetic rats. Eur. J. Pharmacol., 2017, 799, 160-170.
[http://dx.doi.org/10.1016/j.ejphar.2017.02.022] [PMID: 28213289]
[23]
Srivastava, R.A.K.; Ali, W.; Cefalù, A.B.; Noto, D.; Averna, M.R. A combination of metformin, quercetin, and curcumin restores HDL function and improves atherosclerosis burden in LDLr-/- /Ob.Ob Leptin-/- and LDLr-/- mice by attenuating insulin resistance, hyperglycemia, and low-grade inflammation. Arteriosclerosis, Thrombosis, and Vascular Biology, 2013, 33(Suppl 1)
[24]
Alhemiary, N.A.F. Derivative spectrophotometric and HPLC validated methods for simultaneous determination of metformin and glibenclamide in combined dosage form. Orient. J. Chem., 2014, 30(4), 1507-1516.
[http://dx.doi.org/10.13005/ojc/300408]
[25]
Shidhaye, S.; Nalawade, V.; Peepliwal, A.; Inamdar, B.; Rao, A.; Haria, B. A study to determine the pharmacokinetic parameters of newly developed sustained release metformin dry suspension in rabbits. Int. J. Pharm. Technol., 2016, 8(1), 10472-10483.
[26]
Chhetri, H.P.; Thapa, P.; Van Schepdael, A. Simple HPLC-UV method for the quantification of metformin in human plasma with one step protein precipitation. Saudi Pharm. J., 2014, 22(5), 483-487.
[http://dx.doi.org/10.1016/j.jsps.2013.12.011] [PMID: 25473337]
[27]
Al Bratty, M.; Alhazmi, H.; Javed, S.; Lalitha, K. Development and validation of LC–MS/MS method for simultaneous determination of metformin and four gliptins in human plasma. Chromatographia, 2017.
[http://dx.doi.org/10.1007/s10337-017-3288-0]
[28]
Iqbal, M.; Ezzeldin, E.; Al-Rashood, K.A.; Asiri, Y.A.; Rezk, N.L. Rapid determination of canagliflozin in rat plasma by UHPLC-MS/MS using negative ionization mode to avoid adduct-ions formation. Talanta, 2015, 132, 29-36.
[http://dx.doi.org/10.1016/j.talanta.2014.08.041] [PMID: 25476275]
[29]
Iqbal, M.; Khalil, N.Y.; Alanazi, A.M.; Al-Rashood, K.A. A simple and sensitive high performance liquid chromatography assay with a fluorescence detector for determination of canagliflozin in human plasma. Anal. Methods, 2015, 7(7), 3028-3035.
[http://dx.doi.org/10.1039/C5AY00074B]
[30]
Hanif, M.; Akhtar, M.F.; Naeem, S.; Wahid, M.; Shehzad, M.A.; Saadullah, M.; Nasir, B.; Afzal, S. Development and validation of a new HPLC method for the detection of 5- fluorouracil in mobile phase and in plasma. Curr. Pharm. Anal., 2017, 14(1)
[http://dx.doi.org/10.2174/1573412912666160922124552]
[31]
Li, Q.; Yang, Y.; Shi, G.; Zhang, J.; Li, G.; Sui, Y.; Tang, Y.; Gu, J. Simultaneous quantification of simvastatin and simvastatin acid in human plasma with a highly sensitive LC-ESI-MS/MS method: application to a pharmacokinetic study in healthy chinese volunteers with a fixed dose of simvastatin and extended-release niacin combination tablet. Curr. Pharm. Anal., 2016, 12(2), 96-106.
[http://dx.doi.org/10.2174/1573412911666150630182218]
[32]
Food and Drug Administration.Guidance for Industry: Bioanalytical Method Validation. U.S. Department of Health and Human Services; No. May. , 2001, pp. 4-10.
[33]
Zhang, Y.; Huo, M.; Zhou, J.; Xie, S. PKSolver: An Add-in Program for Pharmacokinetic and Pharmacodynamic Data Analysis in Microsoft Excel., 2010.
[34]
Devineni, D.; Cr, C.; Ariyawansa, J.; Weiner, S.; Shalayda, K.; Murphy, J.; Na, D.; Wajs, E. Bioequivalence of canagliflozin/metformin immediate release fixed-dose combination tablets compared with concomitant administration of single components of canagliflozin and metformin in healthy fed participants. J. Bioequivalence Bioavailab., 2014, 6(6), 6.
[35]
Oliveira, E.J.; Watson, D.G. In vitro glucuronidation of kaempferol and quercetin by human UGT-1A9 microsomes. FEBS Lett., 2000, 471(1), 1-6.
[http://dx.doi.org/10.1016/S0014-5793(00)01355-7] [PMID: 10760502]
[36]
Li, Y.; Wang, M.; Zhi, P.; You, J.; Gao, J-Q. Metformin synergistically suppress tumor growth with doxorubicin and reverse drug resistance by inhibiting the expression and function of P-glycoprotein in MCF7/ADR cells and xenograft models. Oncotarget, 2017, 9(2), 2158-2174.
[PMID: 29416762]
[37]
Hsiu, S-L.; Hou, Y-C.; Wang, Y-H.; Tsao, C-W.; Su, S-F.; Chao, P-D.L. Quercetin significantly decreased cyclosporin oral bioavailability in pigs and rats. Life Sci., 2002, 72(3), 227-235.
[http://dx.doi.org/10.1016/S0024-3205(02)02235-X] [PMID: 12427482]


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Article Details

VOLUME: 16
ISSUE: 6
Year: 2020
Published on: 30 June, 2020
Page: [752 - 762]
Pages: 11
DOI: 10.2174/1573412915666190312161823
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