Received for publication September 28, 2005.
Revised January 19, 2006.
Accepted for publication January 31, 2006.

Effect of P-glycoprotein on intestinal absorption and brain penetration of anti-allergic agent bepotastine besilate

Abstract

The anti-allergic agent bepotastine besilate is a non-sedating, second-generation H1-antagonist with high oral absorption and negligible distribution into brain. To clarify the role of P-gp in the pharmacokinetics of bepotastine, the intestinal absorption and brain penetration studies were performed. [¹⁴C]Bepotastine transport in P-gp overexpressed LLC-PK1 cells indicated that bepotastine was a substrate of P-gp. The affinity of bepotastine to P-gp estimated by ATPase activity assay was low with Km value of 1.25 mM. Following intravenous administration, the brain-to-plasma free concentration ratio in mdr1-knockout mice was three times higher than that in wild-type mice. The in situ intestinal absorption studies of [¹⁴C]bepotastine in rats demonstrated a clear regional difference, showing highest permeability at upper part of small intestine with a decreasing permeability in descending part of small intestine. The apparent absorption rate constant (ka) of [¹⁴C]bepotastine in the small intestine was greatly increased by cyclosporin A and verapamil, especially in the distal portion, and the site-specific absorption of [¹⁴C]bepotastine disappeared. The concentration dependence of ka of [¹⁴C]bepotastine was observed with a higher ka at higher concentration (20 mM) compared with that at lower concentration (1 µM). In conclusion, bepotastine is a substrate for P-gp and P-gp clearly limited the brain distribution of bepotastine, while the effect of P-gp on intestinal absorption of bepotastine was minimal presumably due to high membrane permeability at the upper region of small intestine where P-gp is less expressed. Such intestinal absorption property of bepotastine is distinctly different from the low membrane permeable P-gp substrate fexofenedine.

Key words: ABC transporters, absorption, blood-CNS transport, intestinal transport, mass spectrometry, membrane transport, oral absorption, p-glycoprotein, pharmacokinetics