Reduced Oral Bioavailability and Altered Pharmacokinetics of Saquinavir by Co-administration with Biochanin A in Rats

Abstract

The study was aim to assess the impact of biochanin A on the oral bioavailability and pharmacokinetics (PK) of saquinavir (SQV), a substrate of P-glycoprotein (P-gp), in rats. 10 male rats were randomized into 2 groups of equal size, and administered orally 30 mg/kg SQV with or without 20 mg/kg biochanin A. The PK of SQV was assessed using non-compartmental analysis. Results revealed that the area under the plasma concentration-time curve of SQV from time zero to time infinity (AUC_0-∞) was reduced by 51.39% by biochanin A (P=0.038); while the apparent systemic clearance (CL/F) was increased by 87.62% (P=0.028). Double peak phenomenon was observed in the plasma SQV profiles. Biochanin A increased the first peak, yet decreased the second peak of plasma SQV levels. Our study demonstrates that biochanin A can significantly reduce SQV oral bioavailability and alter SQV PK profiles in rats. Findings in this study suggest a precaution in the clinic when SQV is administered with dietary/herbal supplements that contain biochanin A.

Key words

absorption - antiviral drugs - drug-drug interaction - P-glycoprotein

• References

• 1 WHO. “Consolidation Guidelines on The Use of Antiretroviral Drugs for Treating and Preventing HIV Infection”. World Health Organization; 2013
• 2 Noble S, Faulds D. Saquinavir. A review of its pharmacology and clinical potential in the management of HIV infection. Drugs 1996; 52: 93-112
• 3 Wacher VJ, Silverman JA, Zhang Y et al. Role of P-glycoprotein and cytochrome P450 3A in limiting oral absorption of peptides and peptidomimetics. Journal of pharmaceutical sciences 1998; 87: 1322-1330
• 4 Roche Laboratories. Roche Product for Fortovase (saquinavir). Nutley, NJ: Roche Laboratories; 2001
• 5 Mouly SJ, Paine MF, Watkins PB. Contributions of CYP3A4, P-glycoprotein, and serum protein binding to the intestinal first-pass extraction of saquinavir. Journal of Pharmacology and Experimental Therapeutics 2004; 308: 941-948
• 6 Usansky HH, Hu P, Sinko PJ. Differential roles of P-glycoprotein, multidrug resistance-associated protein 2, and CYP3A on saquinavir oral absorption in Sprague-Dawley rats. Drug Metabolism and Disposition 2008; 36: 863-869
• 7 Middleton E, Kandaswami C, Theoharides TC. The effects of plant flavonoids on mammalian cells: implications for inflammation, heart disease, and cancer. Pharmacological reviews 2000; 52: 673-751
• 8 Zhang S, Morris ME. Effects of the flavonoids biochanin A, morin, phloretin, and silymarin on P-glycoprotein-mediated transport. Journal of Pharmacology and Experimental Therapeutics 2003; 304: 1258-1267
• 9 Zhang S, Morris ME. Effect of the flavonoids biochanin A and silymarin on the P-glycoprotein-mediated transport of digoxin and vinblastine in human intestinal Caco-2 cells. Pharmaceutical research 2003; 20: 1184-1191
• 10 Srinivas NR. Biochanin A: understanding the complexities in the paradoxical drug–drug interaction potential. European journal of drug metabolism and pharmacokinetics 2015; 40: 119-125
• 11 Peng SX, Ritchie DM, Cousineau M et al. Altered oral bioavailability and pharmacokinetics of P-glycoprotein substrates by coadministration of biochanin A. Journal of pharmaceutical sciences 2006; 95: 1984-1993
• 12 Singh SP, Wahajuddin Raju KS. et al. Reduced bioavailability of tamoxifen and its metabolite 4-hydroxytamoxifen after oral administration with biochanin A (an isoflavone) in rats. Phytotherapy research: PTR 2012; 26: 303-307
• 13 Kim S-A, Kim S-W, Choi H-K et al. Enhanced systemic exposure of saquinavir via the concomitant use of curcumin-loaded solid dispersion in rats. European Journal of Pharmaceutical Sciences 2013; 49: 800-804
• 14 Vyas TK, Shahiwala A, Amiji MM. Improved oral bioavailability and brain transport of Saquinavir upon administration in novel nanoemulsion formulations. International journal of pharmaceutics 2008; 347: 93-101
• 15 Washington CB, Wiltshire HR, Man M et al. The disposition of saquinavir in normal and P-glycoprotein deficient mice, rats, and in cultured cells. Drug metabolism and disposition: the biological fate of chemicals 2000; 28: 1058-1062
• 16 Liang G, Li N, Ma L et al. Effect of quercetin on the transport of ritonavir to the central nervous system in vitro and in vivo. Acta pharmaceutica (Zagreb, Croatia) 2016; 66: 97-107
• 17 Buchanan CM, Buchanan NL, Edgar KJ et al. Pharmacokinetics of saquinavir after intravenous and oral dosing of saquinavir: hydroxybutenyl-beta-cyclodextrin formulations. Biomacromolecules 2008; 9: 305-313
• 18 Hirunpanich V, Sato H. Docosahexaenoic acid (DHA) inhibits saquinavir metabolism in-vitro and enhances its bioavailability in rats. The Journal of pharmacy and pharmacology 2006; 58: 651-658
• 19 Kim AE, Dintaman JM, Waddell DS et al. Saquinavir, an HIV protease inhibitor, is transported by P-glycoprotein. Journal of Pharmacology and Experimental Therapeutics 1998; 286: 1439-1445
• 20 Zhang S, Sagawa K, Arnold RD et al. Interactions between the flavonoid biochanin A and P-glycoprotein substrates in rats: In vitro and in vivo. Journal of pharmaceutical sciences 2010; 99: 430-441
• 21 An G, Morris ME. Effects of the isoflavonoid biochanin A on the transport of mitoxantrone in vitro and in vivo. Biopharm Drug Dispos 2010; 31: 340-350
• 22 Chieli E, Romiti N, Cervelli F et al. Effects of flavonols on P-glycoprotein activity in cultured rat hepatocytes. Life sciences 1995; 57: 1741-1751
• 23 Yoo HH, Lee M, Chung HJ et al. Effects of diosmin, a flavonoid glycoside in citrus fruits, on P-glycoprotein-mediated drug efflux in human intestinal Caco-2 cells. Journal of agricultural and food chemistry 2007; 55: 7620-7625
• 24 Youdim KA, Shukitt-Hale B, Joseph JA. Flavonoids and the brain: interactions at the blood-brain barrier and their physiological effects on the central nervous system. Free Radical Biology and Medicine 2004; 37: 1683-1693
• 25 Su Y, Zhang X, Sinko PJ. Human organic anion-transporting polypeptide OATP-A (SLC21A3) acts in concert with P-glycoprotein and multidrug resistance protein 2 in the vectorial transport of Saquinavir in Hep G2 cells. Mol Pharm 2004; 1: 49-56
• 26 Pathak SM, Musmade P, Dengle S et al. Enhanced oral absorption of saquinavir with methyl-beta-cyclodextrin-preparation and in vitro and in vivo evaluation. European Journal of Pharmaceutical Sciences 2010; 41: 440-451
• 27 Pathak SM, Kumar AR, Subramanian G et al. Development and validation of a reversed-phase liquid chromatographic method with fluorescence detection for the study of Saquinavir pharmacokinetics in rat plasma. Analytica chimica acta 2007; 594: 248-256
• 28 Fröhlich M, Burhenne J, Martin-Facklam M et al. Oral contraception does not alter single dose saquinavir pharmacokinetics in women. British Journal of Clinical Pharmacology 2004; 57: 244-252
• 29 Ha HR, Follath F, Bloemhard Y et al. Determination of saquinavir in human plasma by high-performance liquid chromatography. Journal of Chromatography B: Biomedical Sciences and Applications 1997; 694: 427-433
• 30 Kupferschmidt HH, Fattinger KE, Ha HR et al. Grapefruit juice enhances the bioavailability of the HIV protease inhibitor saquinavir in man. British journal of clinical pharmacology 1998; 45: 355-359
• 31 Davies NM, Takemoto JK, Brocks DR et al. Multiple peaking phenomena in pharmacokinetic disposition. Clinical pharmacokinetics 2010; 49: 351-377
• 32 Agoram B, Woltosz WS, Bolger MB. Predicting the impact of physiological and biochemical processes on oral drug bioavailability. Advanced drug delivery reviews 2001; 50: S41-S67
• 33 Wada S, Kano T, Mita S et al. The role of inter-segmental differences in P-glycoprotein expression and activity along the rat small intestine in causing the double-peak phenomenon of substrate plasma concentration. Drug metabolism and pharmacokinetics 2013; 28: 98-103
• 34 Murakami T, Takano M. Intestinal efflux transporters and drug absorption. Expert opinion on drug metabolism & toxicology 2008; 4: 923-939
• 35 Takano M, Yumoto R, Murakami T. Expression and function of efflux drug transporters in the intestine. Pharmacology & therapeutics 2006; 109: 137-161
• 36 Takara K, Ohnishi N, Horibe S et al. Expression profiles of drug-metabolizing enzyme CYP3A and drug efflux transporter multidrug resistance 1 subfamily mRNAS in small intestine. Drug metabolism and disposition: the biological fate of chemicals 2003; 31: 1235-1239
• 37 Mitschke D, Reichel A, Fricker G et al. Characterization of cytochrome P450 protein expression along the entire length of the intestine of male and female rats. Drug Metabolism and Disposition 2008; 36: 1039-1045
• 38 Arora S, Taneja I, Challagundla M et al. In vivo prediction of CYP-mediated metabolic interaction potential of formononetin and biochanin A using in vitro human and rat CYP450 inhibition data. Toxicology letters 2015; 239: 1-8