Influence of hesperetin on the pharmacokinetics of diltiazem in rats

Ravindra Babu Pingili; Surya Sandeep Mullapudi; Sridhar Vemulapalli; Naveen Babu Kilaru

doi:10.7324/JAPS.2023.118669

Abstract

Cytochrome P-450 3A4 (CYP3A4) and P-GP substrates exhibit poor bioavailability. Diltiazem is a benzothiazepine derivative used in various cardiovascular conditions. It is a heart muscle and blood vessel relaxant that improves blood pumping to the heart and from the heart. It has low bioavailability because it is a substrate of CYP3A4 and P-GP. Hesperetin (a flavanone) inhibited CYP3A4 and P-GP in previous investigations. The major goal of this research was to see how hesperetin affected diltiazem pharmacokinetics (PK) in rats and employing everted intestinal sac. Male Wistar rats were given diltiazem (15 mg/kg) alone or in combination with hesperetin (12.5, 25, and 50 mg/kg) once daily for 15 days to hesperetin-pretreated animals. Blood samples were collected on the 1st day in a single-dose PK study and on the 15th day in multiple-dosage PK studies. In vitro, diltiazem was incubated with rat-everted intestinal sacs in the presence and absence of hesperetin and conventional P-GP blockers. Diltiazem Cmax, area under the curve, and half-life (T1/2) rose two-fold in rats pretreated with Hesperetin compared to the diltiazem control group, although Tmax did not alter significantly. The value of Mean Residence Time increased by 37% to 47%. There has been a significant reduction in clearing and distribution rates. The results of an in vitro study showed that the transport of diltiazem was significantly increased in the presence of hesperetin and standard P-GP inhibitors. The current study found that hesperetin significantly increased diltiazem systemic absorption by inhibiting CYP3A4 and P-GP.

Keyword: Diltiazem hesperetin CYP3A4 P-glycoprotein bioavailability pharmacokinetics

Citation:

Pingili RB, Mullapudi SS, Vemulapalli S, Kilaru NB. Influence of hesperetin on the pharmacokinetics of diltiazem in rats. J Appl Pharm Sci, 2023. https://doi.org/10.7324/JAPS.2023.118669

Copyright: © The Author(s). This is an open-access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Reference

Babu PR, Babu KN, Peter PL. Influence of quercetin on the pharmacokinetics of ranolazine in rats and in vitro models. Drug Dev Ind Pharm, 2013; 39:873-9. https://doi.org/10.3109/03639045.2012.707209

Barthe L, Woodley J, Houin G. Gastrointestinal absorption of drugs: methods and studies. Fundam Clin Pharmacol, 1999; 13:154-68. https://doi.org/10.1111/j.1472-8206.1999.tb00334.x

Buckley MMT, Grant SM, Goa KL, McTabish D, Sorkin EM. Diltiazem: a reappraisal of its pharmacological properties and therapeutic use. Drugs, 1990; 39:757-806. https://doi.org/10.2165/00003495-199039050-00009

Capraro J, Clemente A, Rubio LA, Magni C, Scarafoni A, Duranti M. Assessment of the lupin seed glucose-lowering protein intestinal absorption by using in vitro and ex vivo models. Food Chem, 2011; 125:1279-83. https://doi.org/10.1016/j.foodchem.2010.10.073

Chaffman M, Brogden RN. Diltiazem: a review of its pharmacological properties and therapeutic efficacy. Drugs, 1985; 29:387-454. https://doi.org/10.2165/00003495-198529050-00001

Challa VR, Babu PR, Challa SR, Johnson B, Maheswari C. Pharmacokinetic interaction study between quercetin and valsartan in rats and in vitro models. Drug Dev Ind Pharm, 2013; 39:865-72. https://doi.org/10.3109/03639045.2012.693502

Choi EJ, Ahn WS. Neuroprotective effects of chronic hesperetin administration in mice. Arch Pharm Res, 2008; 31:1457-62. https://doi.org/10.1007/s12272-001-2130-1

Choi DH, Choi JS, Li C, Choi JS. Effects of simvastatin on the pharmacokinetics of diltiazem and its main metabolite, desacetyldiltiazem, after oral and intravenous administration in rats: possible role of P-glycoprotein and CYP3A4 inhibition by simvastatin. Pharmacol Rep, 2011; 63:1574-82. https://doi.org/10.1016/S1734-1140(11)70724-1

Choi JS, Han HK. Pharmacokinetic interaction between diltiazem and morin, a flavonoid, in rats. Pharmacol Res, 2005a; 52:386-91. https://doi.org/10.1016/j.phrs.2005.05.011

Choi JS, Han HK. Enhanced oral exposure of diltiazem by the concomitant use of naringin in rats. Int J Pharm, 2005b; 305:122-8. https://doi.org/10.1016/j.ijpharm.2005.09.004

Choi JS, Li X. Enhanced diltiazem bioavailability after oral administration of diltiazem with quercetin to rabbits. Int J Pharm, 2005c; 297:1-8. https://doi.org/10.1016/j.ijpharm.2004.12.004

Choi JS, Piao YJ, Han HK. Pharmacokinetic interaction between fluvastatin and diltiazem in rats. Biopharm Drug Dispos, 2006; 27:437-41. https://doi.org/10.1002/bdd.521

Dixon RA, Steele CL. Flavonoids and isoflavonoids-a gold mine for metabolic engineering. Trends Plant Sci, 1999; 4:394-400. https://doi.org/10.1016/S1360-1385(99)01471-5

Homsy W, Caille G, du Souich P. The site of absorption in the small intestine determines diltiazem bioavailability in the rabbit. Pharm Res, 1995a; 12:1722-6. https://doi.org/10.1023/A:1016217822770

Homsy W, Lefebvre M, Caille G, du Souich P. Metabolism of diltiazem in hepatic and extrahepatic tissues of rabbits: in vitro studies. Pharm Res, 1995b; 12:609-14. https://doi.org/10.1023/A:1016226601988

Hong SP, Choi DH, Choi JS. Effects of resveratrol on the pharmacokinetics of diltiazem and its major metabolite, desacetyldiltiazem, in Rats. Cardiovasc Ther, 2008; 26:269-75. https://doi.org/10.1111/j.1755-5922.2008.00060.x

Hong SP, Yang JS, Han JY, Ha SI, Chung JW, Koh YY, Chang KS, Choi DH. Effects of lovastatin on the pharmacokinetics of diltiazem and its main metabolite, desacetyldiltiazem, in rats: possible role of cytochrome P450 3A4 and P-glycoprotein inhibition by lovastatin. J Pharm Pharmacol, 2011; 63:129-35 https://doi.org/10.1111/j.2042-7158.2010.01160.x

Kallem RR, Ramesh M, Seshagirirao JVLN. Validated LC-ESI-MS/ MS method for simultaneous quantitation of felodipine and metoprolol in rat plasma: application to a pharmacokinetic study in rats. Biomed Chromatogr, 2013; 27:784-91. https://doi.org/10.1002/bmc.2861

Kharasch ED, Bedynek PS, Walker A. Mechanism of ritonavir changes in methadone pharmacokinetics and pharmacodynamics. II. ritonavir effects on CYP3A and pglycoprotein activities. Clin Pharmacol Ther, 2008; 84:506-12. https://doi.org/10.1038/clpt.2008.102

Kolars JC, Schmiedlin RP, Dobbins WO, Schuetz J, Wrighton SA, Watkins PB. Heterogeneity of cytochrome P450IIIA expression in rat gut epithelia. Gastroenterology, 1992; 102:1186-98. https://doi.org/10.1016/0016-5085(92)90756-O

Kumar GN, Rodrigues AD, Buko AM, Denissen JF. Cytochrome P450 - mediated metabolism of the HIV-1 protease inhibitor ritonavir (ABT - 538) in human liver microsomes. J Pharmacol Exp Ther, 1996; 277:423-31.

Lee YH, Lee MH, Shim CK. Pharmacokinetics of diltiazem and deacetyldiltiazem in rats. Int J Pharm, 1991; 76:71-6. https://doi.org/10.1016/0378-5173(91)90345-O

Lefebvre M, Homsy W, Caille G, du Souich P. First-pass metabolism of diltiazem in anesthetized rabbits: role of extrahepatic organs. Pharm Res, 1996; 13:124-8. https://doi.org/10.1023/A:1016097805003

Li F, Lu J, Ma X. CPY3A4-mediated lopinavir bioactivation and its inhibition by ritonavir. Drug Metab Dispos, 2012; 40:18-24. https://doi.org/10.1124/dmd.111.041400

Li K, Zhang X, Zhao F. HPLC determination of diltiazem in human plasma and its application to pharmacokinetics in humans. Biomed Chromatogr, 2003; 17(8):522-5. https://doi.org/10.1002/bmc.270

Pichard LG, Gillet G, Fabre I, Dalet-Beluche I, Bonfils C, Thenot JP, Maurel P. Identification of the rabbit and human cytochromes P-450IIIA as the major enzymes involved in the Ndemethylation of diltiazem. Drug Metab Dispos, 1990; 18:711-9.

Pool PE. Diltiazem. In: Messerli FH (ed.). Cardiovascular drug therapy. 2nd edition, Saunders, Philadelphia, PA, pp 931-71, 1996.

Ravindra BP, Vemulapalli S, Mullapudi SS, Nuthakki S, Pendyala S, Kilaru N. Pharmacokinetic interaction study between flavanones (hesperetin, naringenin) and rasagiline mesylate in wistar rats. Drug Dev Ind Pharm, 2016; 42(7):1110-7. https://doi.org/10.3109/03639045.2015.1115868

Saeki T, Ueda K, Tanigawara Y, Hori R, Komano T. P-glycoprotein- mediated transcellular transport of MDR-reversing agents. FEBS Lett, 1993; 324:99-102. https://doi.org/10.1016/0014-5793(93)81540-G

Sridhar V, Surya Sandeep M, Ravindra BP, Naveen BK. Evaluation of first-pass cytochrome P4503A (CYP3A) and P-glycoprotein activities using felodipine and hesperetin in combination in Wistar rats and everted rat gut sacs in vitro. Phytother Res, 2014; 28:699-705. https://doi.org/10.1002/ptr.5040

Surya SM, Sridhar V, Puneeth Y. Enhanced oral bioavailability of felodipine by naringenin in Wistar rats and inhibition of P-glycoprotein in everted rat gut sacs in vitro. Drug Dev Ind Pharm, 2014; 40:1371-7. https://doi.org/10.3109/03639045.2013.819885

Wacher VJ, Salphati L, Benet LZ. Active secretion and enterocytic drug metabolism barriers to drug absorption. Adv Drug Deliv Rev, 2001; 46:89-102. https://doi.org/10.1016/S0169-409X(00)00126-5

Watkins PB, Wrighton SA, Schuetz EG, Molowa DT, Guzelian PS. Identification of glucocorticoid-inducible cytochromes P-450 in the intestinal mucosa of rats and man. J Clin Invest, 1987; 80:1029-36. https://doi.org/10.1172/JCI113156

Weir MR. Diltiazem: ten years of clinical experience in the treatment of hypertension. J Clin Pharmacol, 1995; 35:220-32. https://doi.org/10.1002/j.1552-4604.1995.tb04051.x

Yeung PK, Feng JDZ, Buckley SJ. Pharmacokinetics and hypotensive effect of diltiazem in rabbits: comparison of diltiazem with its major metabolites. J Pharm Pharmacol, 1998; 50:1247-53. https://doi.org/10.1111/j.2042-7158.1998.tb03341.x

Yusa K, Tsuruo T. Reversal mechanism of multidrug resistance by verapamil: direct binding of verapamil to P-glycoprotein on specific sites and transport of verapamil outward across the plasma membrane of K562/ ADM cells. Cancer Res, 1989; 49:5002-6.

Abstract

HTML Full Text

Reference

Article Metrics

Related Search

Citiaion Alert By Google Scholar

Similar Articles