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Keywords:

Science & Technology, Life Sciences & Biomedicine, Pharmacology & Pharmacy, 1115 Pharmacology and Pharmaceutical Sciences, 3214 Pharmacology and pharmaceutical sciences

Abstract:

Domperidone is a dopamine D2-receptor antagonist, which has been marketed in Europe as a prokinetic and anti-emetic drug. Previously, it has been reported that domperidone is extensively metabolized (mainly by CYP3A)1 and is a substrate of P-glycoprotein (P-gp)2. However, to our knowledge, there is no literature data on the hepatic uptake of domperidone. Therefore, the aim of the present study was to investigate whether hepatic uptake transporter(s) are involved in the transport of domperidone into hepatocytes. Domperidone disposition was assessed using rat and human suspended hepatocytes. Both in rat and human hepatocytes, domperidone (5 µM) uptake was very rapid, with equilibrium of accumulation reached already after 0.5 min. The mean (± SD) accumulation rate of domperidone in rat and human hepatocytes was 2603 ± 339 and 2040 ± 789 pmol/min/million cells, respectively. Moreover, uptake was temperature-dependent, with mean (± SD) uptake rates at 4 °C of 963 ± 181 pmol/min/million cells and 380 ± 93 pmol/min/million cells in rat and human hepatocytes, respectively. When the cells were pretreated with 50 µM of the Organic Anion Transporting Polypeptide (OATP/Oatp; human/rat) inhibitor rifampicin, no significant effects were observed. However, co-incubation with aminobenzotriazole (ABT; 500 µM; CYP inhibitor) significantly (p < 0.05) increased domperidone accumulation after 10 min by 141.4 ± 8.6 %. Concentration-dependent (0.1 – 50 µM) uptake kinetics of domperidone were described by a Km and Vmax value in cryopreserved rat hepatocytes (n = 1) of 51 ± 15 µM and 23407 ± 3936 pmol/min/million cells, respectively. In rat hepatocytes, 100 and 200 µM fluoxetine (inhibitor of the Organic Cation Transporter; OCT/Oct) decreased the domperidone accumulation to 85.2 ± 5.5 and 27.6 ± 3.0 %, respectively, compared to the control, suggesting possible Oct-mediated uptake of domperidone. On the contrary, co-incubation of domperidone with Ntcp (Sodium Taurocholate Co-transporting Polypeptide) or other Oatp inhibitors showed no effects on domperidone uptake. In human hepatocytes, both fluoxetine (100 µM) and taurocholic acid (inhibitor of NTCP/Ntcp; 50 µM) decreased the domperidone uptake to 50 ± 10 and 77 ± 8 %, respectively, compared to the control. Known P-gp inhibitors, valspodar, zosuquidar and digoxin increased the accumulation of domperidone, as reported previously. In conclusion, our results suggest that domperidone hepatic uptake is transporter-mediated by OCT/Oct and/or Ntcp in rat and human hepatocytes. 1. Simard, C. et al. Identification of the cytochrome P450 enzymes involved in the metabolism of domperidone. Xenobiotica. 34, 1013–23 2. Balayssac, D., Authier, N., Cayre, A. & Coudore, F. Does inhibition of P-glycoprotein lead to drug-drug interactions? Toxicology Letters 156, 319–329 (2005).