Vol. 29, Issue 1, 54-59, January 2001

The Transport of a Reversible Proton Pump Antagonist, 5,6-Dimethyl-2-(4-Fluorophenylamino)-4-(1-Methyl-1,2,3,4- Tetrahydroisoquinoline-2-yl) Pyrimidine Hydrochloride (YH1885), across Caco-2 Cell Monolayers

Hong Li, Suk-Jae Chung, Dong-Chool Kim, Hyun-Soo Kim, Jong-Wook Lee, and Chang-Koo Shim

Department of Pharmaceutics, College of Pharmacy, Seoul National University, Seoul, Korea (H.L., S.J.C., C.K.S.); College of Pharmacy, Chungnam National University, Taejon, Korea (D.C.K); and Yuhan Research Center, Yuhan Corporation, Kyunggi-do, Korea (H.S.K., J.W.L.)

5,6-Dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl) pyrimidine hydrochloride (YH1885) is under development as a novel acid pump antagonist by Yuhan Research Center. Previous studies have suggested that the AUC and C_max of orally dosed YH1885 are dose-dependent in the range of 2 to 500 mg/kg. The objective of the present study was to investigate the absorption mechanism of YH1885 using a human colon carcinoma cell line, Caco-2. The cells were grown to confluency on a permeable polycarbonate membrane insert to permit loading of YH1885 on either the apical or basolateral side of the cell monolayer. The flux across the monolayer from the apical to basolateral side was 3 to 5 times greater than that from the basolateral to apical side. The uptake of YH1885 into the Caco-2 cell monolayer was saturable and appeared to be mediated by a high-affinity transporter, with an apparent K_m of 1.47 ± 0.21 µM and a V_max of 25.14 ± 1.16 pmol/cm²/40 s. The apical to basolateral transport across the monolayer was Na⁺-independent, H⁺-sensitive, and energy-dependent. The transport was inhibited significantly by the presence of structural analogs of YH1885 (e.g., YH957, YH1070, and YH1041), some pyrimidine nucleobases (uracil and 5-methyluracil), and nucleobase transport inhibitors (e.g., papaverine, dipyridamole, and phloridzin). These results demonstrate that the apical to basolateral transport of YH1885 across the Caco-2 cell monolayer is partially mediated by a nucleobase transport system, which exhibits high-affinity and energy-dependent properties for YH1885. Saturation of this transport system, in addition to the limited solubility of YH1885 (i.e., ~5.3 µM), appears to contribute to the dose-dependent bioavailability of the drug.