Natural Furanocoumarin as Potential Oral Absorption Enhancer

Abstract:

Bioavailability of orally administered drugs can be influenced by many factors. Poor drug absorption across the intestinal membrane is one of the factors that contribute to low bioavailability of drugs. It has been suggested that the metabolism/active efflux in the small intestine is involved in the poor absorption of many drugs. Intestinal CYP3A4 and P-gp work coordinately to reduce the intracellular concentration of drugs. Recently, bioenhancers have been identified and extensively studied. The aim of this study was to evaluate natural furanocoumarins found in juices of common lime and kaffir lime as the potential enhancers for oral delivery by means of modulating CYP3A4 and/or P-gp activities. The role of isolated furanocoumarins on CYP3A4 was assessed by testosterone 6β-hydroxylation reaction, while the effect on P-gp was investigated using R123 and CAM uptake studies in Caco-2, as well as LLC-PK₁ and LLC-GA5-Col300. In the present study, we demonstrated that isopimpinellin isolated from common lime is the best CYP3A4 inhibitor among 4 isolated furanocoumarins, implying that isopimpinellin would possibly act as a bioenhancer by inhibiting pre-systemic metabolism. 6’,7’-Dihydroxybergamottin found in kaffir lime is a dual inhibitor of CYP3A4 and P-gp, suggest that it could potentially be used as a bioenhancer by inhibiting both pre-systemic metabolism and efflux mechanism. However, in vivo study should be further conducted to confirm these effects in the body.

References

[1] A.S, Darwich, S. Neuhoff, M. Jamei, A. Rostami-Hodjegan, Interplay of metabolism and transport in determining oral drug absorption and gut wall metabolism: a simulation assessment using the Advanced Dissolution, Absorption, Metabolism (ADAM), model, Curr. Drug Metab. 11 (2010) 716-729.

DOI: 10.2174/138920010794328913

[2] F. Thiebaut , T. Tsuruo, H. Hamada, M.M. Gottesman, I. Pastan, M.C. Willingham, Cellular localization of the multidrug-resistance gene product P-glycoprotein in normal human tissues, Proc. Natl. Acad. Sci. U. S. A. 84 (1987) 7735-7738.

DOI: 10.1073/pnas.84.21.7735

[3] H. Suzuki, Y. Sugiyama, Role of metabolic enzymes and efflux transporters in the absorption of drugs from the small intestine, Eur. J. Pharm. Sci. 12 (2000) 3-12.

DOI: 10.1016/s0928-0987(00)00178-0

[4] P-A. Billat, R. Emilie, S. Faure, F. Lagarce, Models for drug absorption from the small intestine: where are we and where are we going?, Drug Discov. Today 22 (2017) 761-775.

DOI: 10.1016/j.drudis.2017.01.007

[5] Y. Zhang, L.Z. Benet, The gut as a barrier to drug absorption: combined role of cytochrome P450 3A and P-glycoprotein, Clin. Pharmacokinet. 40 (2001) 159-168.

DOI: 10.2165/00003088-200140030-00002

[6] L.Z. Benet, C.L. Cummins, C.Y. Wu, Unmasking the dynamic interplay between efflux transporters and metabolic enzymes, Int. J. Pharm. 277 (2004) 3-9.

DOI: 10.1016/j.ijpharm.2002.12.002

[7] G. Randhawa, J. S. Kullar, Rajkumar, Bioenhancers from mother nature and their applicability in modern medicine, Int. J. Appl. Basic Med. Res. 1 (2011) 5–10.

DOI: 10.4103/2229-516x.81972

[8] Ajazuddin, A. Alexander A, A. Qureshi A, L. Kumari, P. Vaishnav, M. Sharma, S. Saraf, S. Saraf, Role of herbal bioactives as a potential bioavailability enhancer for Active Pharmaceutical Ingredients, Fitoterapia. 97 (2014) 1-14.

DOI: 10.1016/j.fitote.2014.05.005

[9] B. Peterson, M. Weyers, J.H. Steenekamp, J.D. Steyn, C. Gouws, J.H Hamman, Drug bioavailability enhancing agents of natural origin (bioenhancers) that modulate drug membrane permeation and pre-systemic metabolism, Pharmaceutics. 16 (2019) 1-46.

DOI: 10.3390/pharmaceutics11010033

[10] E. Valenciennes, J. Smadja, J.Y. Conan, Screening for biological activity and chemical composition of Euodia borbonica var. borbonica (Rutaceae), a medicinal plant in Reunion Island, J. Ethnopharmacol. 64 (1999) 283-288.

DOI: 10.1016/s0378-8741(98)00137-8

[11] G. Lehr, T.L. Barry, J. Franolic, P. Glenn, P. Scheiner, LC determination of impurities in methoxsalen drug substance: isolation and identification of isopimpinellin as a major impurity by atmospheric pressure chemical ionization LC/MS and NMR, J. Pharm. Biomed. Anal. 33 (2003) 627-637.

DOI: 10.1016/s0731-7085(03)00353-4

[12] A. Murakami, G. Gao, K. Kim, M. Omura, M. Yano, C. Ito, H. Furukawa, S. Jiwajinda, K. Koshimizu, H. Ohigashi H, Identification of coumarins from the fruit of Citrus hystrix DC as inhibitors of nitric oxide generation in mouse macrophage RAW 264.7 cells, J. Agric. Food Chem.47 (1999) 333-339.

DOI: 10.1021/jf980523e

[13] D. L. Dreyer, P.F. Huey, Coumarins of Citrus macroptera, Phytochemistry. 12 (1973) 3011-3013.

DOI: 10.1016/0031-9422(73)80536-9

[14] Y. Tanigawara, N. Okamura, M. Hirai, M. Yasuhara, K. Ueda, N. Kioka, T. Komano, R. Hori, Transport of digoxin by human P-glycoprotein expressed in a porcine kidney epithelial cell line (LLC-PK1), J. Pharmacol. Exp. Ther. 263 (1992) 840-845.

DOI: 10.1016/s0021-9258(18)35757-0

[15] K. Ueda, N. Okamura, M. Hirai, Y. Tanigawara, T. Saeki, N. Kioka, T. Komano, R. Hori, Human P-glycoprotein transports cortisol, aldosterone, and dexamethasone, but not progesterone. J. Biol. Chem. 267 (1992) 24248-24252.

DOI: 10.1016/s0021-9258(18)35757-0

[16] M.D. Troutman, D.R. Thakker, Rhodamine 123 requires carrier-mediated influx for its activity as a P-glycoprotein substrate in Caco-2 cells, Pharm. Res. 20 (2003) 1192-1199.

[17] O. Legrand, G. Simonin, J.Y. Perrot, R. Zittoun, J.P. Marie, Pgp and MRP activities using calcein-AM are prognostic factors in adult acute myeloid leukemia patients. Blood. 15 (1998) 4480-4488.

DOI: 10.1182/blood.v91.12.4480.412k28_4480_4488

[18] D.J. Greenblatt, Y. Zhao, K. Venkatakrishnan, S.X. Duan, J.S. Harmatz, S.J. Parent, M.H. Court, L.L. von Moltke, Mechanism of cytochrome P450-3A inhibition by ketoconazole, J. Pharm. Pharmacol. 63 (2011) 214-221.

DOI: 10.1111/j.2042-7158.2010.01202.x

[19] M. Li, I.A. de Graaf, E. van de Steeg, M.H. de Jager, G.M. Groothuis, The consequence of regional gradients of P-gp and CYP3A4 for drug-drug interactions by P-gp inhibitors and the P-gp/CYP3A4 interplay in the human intestine ex vivo, Toxicol. in Vitro 40 (2017) 26–33.

DOI: 10.1016/j.tiv.2016.12.002

[20] D.V. Tatiraju, V.B. Bagade, P.J. Karambelkar, V.M. Jadhav, V. Kadam, Natural bioenhancers: an overview, J. Pharmacogn. Phytochem. 2 (2013) 55-60.