INFLUENCE OF P-GLYCOPROTEIN AND CYTOCHROME ISOENZYME-P3A4 ON BIOAVAILABILITY OF ANTICANCER DRUGS WITH CURCUMIN BY IN SITU INTESTINAL PERFUSION IN MALE WISTAR RATS: Influence of P-glycoprotein & CYP3A4 on bioavailability of anti cancer drugs

MANOJ KANNA NALLA; SHANKARAIAH PULIGILLA

doi:10.22159/ajpcr.2019.v12i7.32938

Authors

MANOJ KANNA NALLA Department of Pharmacology, Chaitanya College of Pharmacy Education and Research, Kishanpura, Hanamkonda, Telangana, India.
SHANKARAIAH PULIGILLA Department of Pharmacology, Chaitanya College of Pharmacy Education and Research, Kishanpura, Hanamkonda, Telangana, India.

DOI:

https://doi.org/10.22159/ajpcr.2019.v12i7.32938

Keywords:

P-glycoprotein,, Cytochrome isoenzyme-P3A4,, Drug absorption,, Imatinib,, Intestinal perfusion

Abstract

Objectives: An orally administered anticancer drug has been poor drug absorption; drug resistance and metabolism, which alters the bioavailability of drugs. An in situ intestine perfusion technique is developing under the different perfusion rates in the presence of drug inducers and inhibitors of cytochrome isoenzyme-P (CYP)-3A4 and P-glycoprotein (P-gp) for drug concentrations.

Materials and Methods: The modified in situ intestinal perfusion technique was developed and followed to obtain the portal and hepatic venous blood samples paralleled at different perfusion time and flow rates of 0.05, 0.1, 0.5, and 1.0 mL/min using the imatinib (1 mg/mL) drug alone and in the presence of drug inducer and drug inhibitor for the period of 3 h. The imatinib drug concentrations were assayed using high-pressure liquid chromatography.

Results: The results reveal that the mean imatinib drug concentrations in portal vein were higher than hepatic vein at various perfusion flow rates and time intervals were observed. The area under curve and plasma drug concentrations maximum of imatinib alone absorptions were significantly different between portal and hepatic veins (p<0.05) at the flow rates of 0.5 and 1.0 mL/min and also in the presence of drug inducer and inhibitors that indicating for the considerable hepatic involvement in the presystemic extraction or metabolism of drugs.

Conclusions: The in situ perfusions approach could provide the useful tool for improving the basic understanding of absorption kinetics and hepatic metabolism of drugs in the presence of drug inducers and drug inhibitors (CYP3A4 and P-gp) under the development and facilitating the clinical applications.

Downloads

Download data is not yet available.

References

Agoram B, Woltosz WS, Bolger MB. Predicting the impact of physiological and biochemical processes on oral drug bioavailability. Adv Drug Deliv Rev 2001;50 Suppl 1:S41-67.

Somar M, Crowe A, Hughes J. Distribution of the single nucleotide polymorphism c3435t of mdr1gene among people in Western Australia, Australia. Int J Pharm Pharm Sci 2013;5:470-3.

Shailendra W, Sarita S, Swati R. Bioavailability enhancement by piperine: A review. Asian J Biomed Pharm Sci 2014;4:1-8.

Hermann R, von Richter O. Clinical evidence of herbal drugs as perpetrators of pharmacokinetic drug interactions. Planta Med 2012;78:1458-77.

Van Erp NP, Gelderblom H, Karlsson MO. Influence of CYP3A4 inhibition on the steady-state pharmacokinetics of imatinib. Clin Cancer Res 2007;13:7394-400.

Gschwind HP, Pfaar U, Waldmeier F, Zollinger M, Sayer C, Zbinden P, et al. Metabolism and disposition of imatinib mesylate in healthy volunteers. Drug Metab Dispos 2005;33:1503-12.

Peng B, Lloyd P, Schran H. Clinical pharmacokinetics of imatinib. Clin Pharmacokinet 2005;44:879-94.

Frye RF, Fitzgerald SM, Lagattuta TF, Hruska MW, Egorin MJ. Effect of St John’s wort on imatinib mesylate pharmacokinetics. Clin Pharmacol Ther 2004;76:323-9.

Cortes JE, Egorin MJ, Guilhot F, Molimard M, Mahon FX. Pharmacokinetic/pharmacodynamic correlation and blood-level testing in imatinib therapy for chronic myeloid leukemia. Leukemia 2009;23:1537-44.

Scott LM, Durant P, Leone-Kabler S, Wood CE, Register TC, Townsend A, et al. Effects of prior oral contraceptive use and soy isoflavonoids on estrogen-metabolizing cytochrome P450 enzymes. J Steroid Biochem Mol Biol 2008;112:179-85.

Elgadir MA, Salama M, Adam A. Anti-breast cancer from various natural sources, review. Int J Pharm Pharm Sci 2015;7:44-7.

Sakaeda T, Nakamura T, Okumura K. Pharmacogenetics of drug transporters and its impact on the pharmacotherapy. Curr Top Med Chem 2004;4:1385-98.

Kuhad A, Chopra K. Curcumin attenuates diabetic encephalopathy in rats: Behavioral and biochemical evidences. Eur J Pharmacol 2007;576:34-42.

Yu HY, Lai YR, Kuo TL, Shen YZ. Effects of ethanol on pharmacokinetics and intestinal absorption of paraquat in animals. J Toxicol Sci 1994;19:67-75.

Kukan M. The isolated perfused liver as a tool in drug metabolism studies. In: Woolf TF, editor. Handbook of Drug Metabolism. New York: Marcel Dekker; 1999. p. 425-42.

Doluisio JT, Billups NF, Dittert LW, Sugita ET, Swintosky JV. Drug absorption. I. An in situ rat gut technique yielding realistic absorption rates. J Pharm Sci 1969;58:1196-200.

Blanchard J, Tang LM, Earle ME. Reevaluation of the absorption of carbenoxolone using an in situ rat intestinal technique. J Pharm Sci 1990;79:411-4.

Yorgey KA, Pritchard JF, Renzi NL, Dvorchik BH. Evaluation of drug absorption and presystemic metabolism using an in situ intestinal preparation. J Pharm Sci 1986;75:869-72.

Azuma R, Hirota T, Manabe H, Komuro M, Kiwada H. First-pass of GTS-21 on canine gut wall and liver determined by portal-systemic concentration difference. Eur J Pharm Sci 2001;14:159-65.

Hashimoto Y, Sasa H, Shimomura M, Inui K. Effects of intestinal and hepatic metabolism on the bioavailability of tacrolimus in rats. Pharm Res 1998;15:1609-13.

Bahramsoltani R, Rahimi R, Farzaei MH. Pharmacokinetic interactions of curcuminoids with conventional drugs: A review. J Ethnopharmacol 2017;209:1-2.

Cho YA, Lee W, Choi JS. Effects of curcumin on the pharmacokinetics of tamoxifen and its active metabolite, 4-hydroxytamoxifen, in rats: Possible role of CYP3A4 and P-glycoprotein inhibition by curcumin. Pharmazie 2012;67:124-30.

Fleming I. Cytochrome p450 and vascular homeostasis. Circ Res 2001;89:753-62.

Hukkanen J, Pelkonen O, Raunio H. Expression of xenobiotic-metabolizing enzymes in human pulmonary tissue: Possible role in susceptibility for ILD. Eur Respir J Suppl 2001;32:122s-6s.

Hukkanen J, Pelkonen O, Hakkola J, Raunio H. Expression and regulation of xenobiotic-metabolizing cytochrome P450 (CYP) enzymes in human lung. Crit Rev Toxicol 2002;32:391-411.

Gibbs MA, Hosea NA. Factors affecting the clinical development of cytochrome p450 3A substrates. Clin Pharmacokinet 2003;42:969-84.

Zhang W, Tan TM, Lim LY. Impact of curcumin-induced changes in P-glycoprotein and CYP3A expression on the pharmacokinetics of peroral celiprolol and midazolam in rats. Drug Metab Dispos 2007;35:110-5.

Balabhaskar R, Kumar AR, Selvarajan S, Faridha A, Gunalan G. Potential natural products with anticancer properties and their applications. Asian J Pharm Clin Res 2019;12:27-33.