New BCRP Probe Substrates
December 11, 2012
Newsletter – New BCRP Probe Substrates
SOLVO is Introducing New Probe Substrates for BCRP-related Drug-Drug Interaction Assays on MDCKII-BCRP and Caco2 Monolayers: chlorothiazide and teriflunomide
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Regulatory agencies prefer to see assays where drugs instead of physiological substrates or other substrate chemicals are used as probes. This approach has multiple advantages, since the probe – transporter interaction is pharmacologically more relevant and the inhibition assay yields relevant drug drug interaction data. SOLVO is continuesly developing FDA relevant inhibition assays
with clinically relevant drugs as probe substrates.
Drugs that are substrates of BCRP
might be victims to drug drug interactions where BCRP is inhibited. Especially drugs with a narrow therapeutic index and low oral bioavailability are of concern in this case. Current FDA and EMA recommendations for testing BCRP are based mainly on its role in intestinal absorption
. BCRP is known to have relevance to drug PK and interactions, for BBB
and tumor penetration. Drug candidates need to be screened for in vitro BCRP substrate and inhibition liability.
Finding specific substrate for transporters with broad and overlapping substrate specificities such as the MDR-ABC transporters is always a challenge. It is also a must as some of these transporters like BCRP/ABCG2, MDR1/P-gp/ABCB1 and MRP2/ABCC2 co-localize at multiple physiological barriers of pharmacological importance. Thus, application of chlorothiazide and teriflunomide as specific BCRP probes is a significant advance of the field.
SOLVO is introducing inhibition assessment assays with chlorothiazide (Figures 1 and 2) and teriflunomide (Figures 3 and 4) as probe substrates both in MDCKII-BCRP and Caco-2 monolayers.
BCRP-specific Vectorial Transport of Chlorothiazode
is a thiazid type diuretic drug, which has a low oral bioavailability . As chlorothiazide is basically nonmetabolized this implicates a role of efflux transporter . It was shown using different in vitro
assays, that this drug is transported by BCRP but does not interact with Pgp and MRP2 .
Figure 1. Vectorial transport of chlorothiazide by BCRP transporter in MDCKII-BCRP and MDCKII monolayer assays.
Figure 2. Vectorial transport of chlorothiazide by BCRP transporter in Caco2 monolayer assay.
BCRP-specific Vectorial Transport of Teriflunomide
Leflunomide is a commonly used disease modifying anti-rheumatic drug which is rapidly metabolized to its active form A771726 (teriflunomide
). Based on in vitro
data, both leflunomide and teriflunomide are high affinity substrates of BCRP transporter . Kim and colleagues have shown that BCRP c.421C>A but not the c.34G>A polymorphism affected the plasma levels of teriflunomide. This polymorphism appears to be a major determinant of inter-individual variability in teriflunomide disposition in the body .
Figure 3.Vectorial transport of teriflunomide by BCRP transporter in MDCKII-BCRP and MDCKII monolayer assays.
Figure 4.Vectorial transport of teriflunomide by BCRP transporter in Caco2 monolayer assay.
- Straughn AB, Melikian AP, Meyer MC. Bioavailability of chlorothiazide tablets of humans. J Pharm Sci. 1979 Sep;68(9):1099-102.
- Shugarts S, Benet LZ. The role of transporters in the pharmacokinetics of orally administered drugs.Pharm Res 2009 Sep;26(9):2039-54.
- Beéry et al. ABCG2 modulates chlorothiazide permeability in vitro - characterization of the interaction.Drug Metab. Pharmacokinet.2012;27(3):349-53
- Kis E et al. Leflunomide and its metabolite A771726 are high affinity substrates of BCRP: implications for drug resistance. Ann Rheum Dis. 2009 Jul;68(7):1201-7
- Kim KA et al. Effect of ABCG2 genotypes on the pharmacokinetics of A771726, an active metabolite of prodrug leflunomide, and association of A771726 exposure with serum uric acid level. Eur J Clin Pharmacol. 2011 Feb;67(2):129-34.
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