Pharmacokinetic interaction study of sulphasalazine in healthy subjects and the impact of curcumin as an in vivo inhibitor of BCRP

Abstract

BACKGROUND AND PURPOSEAn ATP-binding cassette (ABC) transporter, breast cancer resistance protein (BCRP)/ABCG2, limits oral bioavailability of sulphasalazine. Here we examined the effect of curcumin, the principal curcuminoid of turmeric, on oral bioavailability of microdoses and therapeutic doses of sulphasalazine in humans. EXPERIMENTAL APPROACHEffects of curcumin were measured on the ATP-dependent sulphasalazine uptake by hBCRP-expressing membrane vesicles and on oral bioavailability of sulphasalazine in wild-type and Bcrp(-/-) mice. Eight healthy Japanese subjects received an oral dose of sulphasalazine suspension (100 mg) or tablets (2 g) alone or after curcumin tablets (2 g). Uptake of sulphasalazine was studied in HEK293 cells transfected with the influx transporter (OATP)2B1. KEY RESULTSCurcumin was a potent hBCRP inhibitor in vitro (Ki 0.70 Ϯ 0.41 mM). Curcumin increased the area under the curve (AUC)0-8 of plasma sulphasalazine eightfold in wild-type mice at 300 and 400 mg·kg -1 , but not in Bcrp(-/-) mice. Curcumin increased AUC0-24 of plasma sulphasalazine 2.0-fold at microdoses and 3.2-fold at therapeutic doses in humans. Non-linearity of the dose-exposure relationship was observed between microdoses and therapeutic doses of sulphasalazine. Sulphasalazine was a substrate for OATP2B1 (Km 1.7 Ϯ 0.3 mM). Its linear index (dose/Km) at the therapeutic dose was high and may saturate OATP2B1. CONCLUSIONS AND IMPLICATIONSCurcumin can be used to investigate effects of BCRP on oral bioavailability of drugs in humans. Besides the limited dissolution, OATP2B1 saturation is a possible mechanism underlying non-linearity in the dose-exposure relationship of sulphasalazine. AbbreviationsABC, ATP-binding cassette; AUC, area under the curve; BCRP, breast cancer resistance protein; CLtot, total body clearance; Ki, inhibition constant Km, Michaelis constant; MRP2, multidrug resistance-associated protein 2; OATP, organic anion-transporting polypeptide; SNP, single nucleotide polymorphism BJP British Journal of Pharmacology

Breast Cancer Resistance Protein Substrate and Inhibition Evaluation: Why, When, and How?

“…The study in question by Adkison et al (2010) used oral sulfasalazine enteric-coated tablets and, in fact, surprisingly showed no significant pharmacokinetic changes with oral coadministration of the BCRP inhibitor, pantoprazole, or a significant genedose effect of the BCRP 421 C.A functional polymorphism. These results stand in stark contrast to three independent clinical studies using oral immediate-release sulfasalazine tablets and/or suspension formulation, where significant 2-to 4-fold increases in sulfasalazine exposure were observed in carriers of the BCRP 421 C.A polymorphism and during coadministration of an oral BCRP inhibitor (Urquhart et al, 2008;Yamasaki et al, 2008;Kusuhara et al, 2012), as well as three independent preclinical studies in Bcrp-knockout mice and rats (Zaher et al, 2006;Shukla et al, 2009;Zamek-Gliszczynski et al, 2012). As discussed by Adkison et al (2010), an accidental flaw in the execution of their study demonstrated the importance of proper formulation selection (suspension or immediate release, but not extended release), rather than disproving the utility of sulfasalazine as a marker of BCRP activity in humans.…”

“…We would also like to comment on the authors' conclusion that sulfasalazine is not as sensitive to BCRP modulation in humans as knockout rodents based on the apparent discordance between the magnitude of oral sulfasalazine exposure increase in Bcrp-knockout rodent studies [23-to 111-fold (Zaher et al, 2006;Shukla et al, 2009;Zamek-Gliszczynski et al, 2012)] and that in human clinical studies [2-to 4-fold (Urquhart et al, 2008;Yamasaki et al, 2008;Kusuhara et al, 2012)]. This difference in Bcrp function between complete genetic ablation in Abcg22/2 animals and partial Bcrp inhibition by gefitinib was also acknowledged in the original publication by Zaher Shukla et al (2009).…”

“…However, we noticed that the authors have missed some critically important concepts when referring to drugs that have complex permeability/efflux and atypical metabolism, whose disposition has been mechanistically uncovered by reverse translation (working from bedside back to the bench). These omissions resulted in the description of sulfasalazine as a poor BCRP substrate in humans, even though it is currently one of the two best available clinical BCRP probes along with rosuvastatin (Urquhart et al, 2008;Yamasaki et al, 2008;Kusuhara et al, 2012).…”

“…However, we noticed that the authors have missed some critically important concepts when referring to drugs that have complex permeability/efflux and atypical metabolism, whose disposition has been mechanistically uncovered by reverse translation (working from bedside back to the bench). These omissions resulted in the description of sulfasalazine as a poor BCRP substrate in humans, even though it is currently one of the two best available clinical BCRP probes along with rosuvastatin (Urquhart et al, 2008;Yamasaki et al, 2008;Kusuhara et al, 2012).The authors selectively used one specific clinical study as "proof" that "sulfasalazine PK was not affected in individuals with impaired BCRP function, nor when coadministered with [a BCRP inhibitor]" (Poirier et al, 2014). The study in question by Adkison et al (2010) used oral sulfasalazine enteric-coated tablets and, in fact, surprisingly showed no significant pharmacokinetic changes with oral coadministration of the BCRP inhibitor, pantoprazole, or a significant genedose effect of the BCRP 421 C.A functional polymorphism.…”

Development of an optimized hyaluronic acid-based lipidic nanoemulsion co-encapsulating two polyphenols for nose to brain delivery

“…However, resveratrol was reported to be affected by the BCRP efflux pump, hence limiting its bioavailability (Scheepens et al, 2010). Curcumin was advantageously reported to lower the expression of p-glycoprotein transporters, as well as inhibit BCRP transporters in vivo (Holland et al, 2006;Nabekura, 2010;Kusuhara et al, 2012), and hence, the combination of curcumin and resveratrol in the same formula is expected to have facilitated the brain delivery of resveratrol. As illustrated in Figure 6, the significantly lower amounts of the two drugs reaching the brain following intranasal administration of their aqueous solution could be ascribed to its rapid mucociliary clearance as well as its possible nasal drainage (Gabal et al, 2014).…”