Subject(s)
Antiparkinson Agents/pharmacokinetics , Bromocriptine/pharmacokinetics , Erythromycin/pharmacology , Liver-Specific Organic Anion Transporter 1/drug effects , Liver-Specific Organic Anion Transporter 1/metabolism , Anti-Bacterial Agents/pharmacology , Cytochrome P-450 CYP3A , Cytochrome P-450 Enzyme System/drug effects , Cytochrome P-450 Enzyme System/metabolism , Dopamine Agonists/pharmacokinetics , HumansABSTRACT
Ticlopidine is sometimes coadministered with ergoloid mesylates or ginkgo biloba in clinical situations. Our objective was to examine the effect of ergoloid mesylates and ginkgo biloba on ticlopidine pharmacokinetics. Ticlopidine, ergoloid mesylates, and ginkgo biloba significantly inhibited the organic anion transporting polypeptide (OATP-B)-mediated uptake of [(3)H]-estrone-3-sulfate in a concentration-dependent manner. When ergoloid mesylates was coadministered with ticlopidine, the ticlopidine area under the plasma drug concentration-time profile (AUC) from 0 to 12 hours was decreased 30% and the peak plasma drug concentration (C(max)) was decreased 29%, compared with ticlopidine administration alone. There were no significant changes in the pharmacokinetic parameters of ticlopidine when it was coadministered with ginkgo biloba. In summary, ergoloid mesylates is a more potent inhibitor of OATP-B than is ginkgo biloba, and it can reduce the oral bioavailability of drugs transported by OATP-B. Ergoloid mesylates markedly decreased the AUC and C(max) of ticlopidine, probably by inhibiting the OATP-B-mediated uptake of ticlopidine during the intestinal absorption phase. The results support a new model of intestinal drug-drug interaction.
Subject(s)
Ginkgo biloba , Organic Anion Transporters/metabolism , Platelet Aggregation Inhibitors/pharmacokinetics , Ticlopidine/pharmacokinetics , Adult , Cell Line , Drug Interactions , Ergoloid Mesylates/pharmacology , Estrone/analogs & derivatives , Estrone/metabolism , Female , Humans , Intestinal Absorption/drug effects , Male , Plant Preparations/pharmacology , Platelet Aggregation Inhibitors/blood , Ticlopidine/bloodABSTRACT
Arsenic-resistant cells (R15), derived from a human lung adenocarcinoma cell line (CL3), were 10-fold more resistant to sodium arsenite (As(III)). Because R15 cells accumulated less arsenic than parental CL3 cells, this arsenic resistance may be due to higher efflux and/or lower uptake of As(III). We therefore compared expression of the multidrug resistance-associated proteins MRP1, MRP2, and MRP3 in these two cell lines. MRP2 expression was 5-fold higher in R15 cells than in CL3 cells, whereas MRP1 and MRP3 expression levels were similar. Furthermore, verapamil and cyclosporin A, inhibitors of multidrug resistance transporters, significantly reduced the efflux of arsenic from R15. Thus, increased arsenic extrusion by MRP2 may contribute to arsenic resistance in R15 cells. We also examined the expression of several aquaglyceroporins (AQPs), which mediate As(III) uptake by cells. Little AQP7 or AQP9 mRNA was detected by reverse transcription-PCR in either cell line, whereas AQP3 mRNA expression was 2-fold lower in R15 cells than in CL3 cells. When AQP3 expression in CL3 cells was knocked down by RNA interference, CL3 cells accumulated less arsenic and became more resistant to As(III). Conversely, overexpression of AQP3 in human embryonic kidney 293T cells increased arsenic accumulation, and the cells were more susceptible to As(III) than 293T cells transfected with vector alone. These results suggest that AQP3 is involved in As(III) accumulation. Taken together, our results suggest that enhanced expression of MRP2 and lower expression of AQP3 are responsible for lower arsenic accumulation in arsenic-resistant R15 cells.
Subject(s)
Aquaporin 3/genetics , Arsenites/pharmacology , Drug Resistance/genetics , Membrane Transport Proteins/genetics , Multidrug Resistance-Associated Proteins/genetics , Sodium Compounds/pharmacology , Aquaglyceroporins/genetics , Cell Line, Tumor , Gene Expression Regulation , Humans , Multidrug Resistance-Associated Protein 2ABSTRACT
Arsenic is an established human carcinogen. The role of aquaglyroporins (AQPs) in arsenic disposition was recently identified. In order to examine whether organic anion transporting polypeptide-C (OATP-C) also plays a role in arsenic transport, OATP-C cDNA was transfected into cells of a human embryonic kidney cell line (HEK-293). Transfection increased uptake of the model OATP-C substrate, estradiol-17beta-D-glucuronide, by 10-fold. In addition, we measured uptake and cytotoxicity of arsenate, arsenite, monomethylarsonate(MMA(V)), and dimethylarsinate (DMA(V)). Transfection of OATP-C increased uptake and cytotoxicity of arsenate and arsenite, but not of MMA(V) or DMA(V). Rifampin and taurocholic acid (a substrate of OATP-C) reversed the increased toxicity of arsenate and arsenite seen in OATP-C-transfected cells. The increase in uptake of inorganic arsenic was not as great as that of estradiol-17beta-D-glucuronide. Our results suggest that OATP-C can transport inorganic arsenic in a (GSH)-dependent manner. However, this may not be the major pathway for arsenic transport.
