Diurnal expression of MRP4 in bone marrow cells underlies the dosing-time dependent changes in the oxaliplatin-induced myelotoxicity

Abstract

the expression and function of some xenobiotic transporters varies according to the time of day, causing the dosing time-dependent changes in drug disposition and toxicity. Multidrug resistanceassociated protein-4 (MRP4), an ATP binding cassette (ABC) efflux transporter encoded by the Abcc4 gene, is highly expressed in bone marrow cells (BMCs) and protects them against xenobiotics, including chemotherapeutic drugs. In this study, we demonstrated that MRP4 was responsible for the extrusion of oxaliplatin (L-OHP), a platinum (Pt)-based chemotherapeutic drug, from BMCs of mice, and that the efflux transporter expression exhibited significant diurnal variation. Therefore, we investigated the relevance of the diurnal expression of MRP4 in BMCs for L-OHPinduced myelotoxicity in mice maintained under standardized light/dark cycle conditions. After intravenous injection of L-OHP, the Pt content in BMCs varied according to the injection time. Lower Pt accumulation in BMCs was detected in mice after injection of L-OHP at the mid-dark phase, during which the expression levels of MRP4 increased. Consistent with these observations, the myelotoxic effects of L-OHP were attenuated when mice were injected with L-OHP during the dark phase. This dosing schedule also alleviated the L-OHP-induced reduction of the peripheral white blood cell count. The present results suggest that the myelotoxicity of L-OHP is attenuated by optimizing the dosing schedule. Diurnal expression of MRP4 in BMCs is associated with the dosing time-dependent changes in L-OHP-induced myelotoxicity. Daily variations in biological functions, such as gene expression and protein synthesis, are thought to be important factors affecting the efficacy and/or toxicity of drugs; a large number of drugs cannot be expected to have the same potency at different administration times 1,2. Consequently, administration of drugs at appropriate times of day can improve the outcome of pharmacotherapy by maximizing their potency and minimizing their toxicity, whereas drug administration at an inappropriate time of day can induce severe side effects. Dosing time-dependent differences in the drug effects are due, at least in part, to 24-h changes in drug disposition such as absorption, distribution, metabolism, and elimination 3-6. ATP binding cassette (ABC) transporters are widely known as energy-dependent efflux pumps that expel cytotoxic substances, including chemotherapeutic drugs. They are expressed in epithelial cells of several organs, including the brain, liver, intestine, and kidney 7 , and function as a barrier to limit intestinal absorption of many drugs and their distribution to different tissues 8. Furthermore, several types of ABC transporters also function in the biliary, intestinal, and renal elimination of drugs 9. The expression and function of some ABC transporters, such as P-glycoprotein (P-gp), multidrug resistance-associated protein 2 (MRP2), and breast cancer-resistant protein (BCRP), exhibit diurnal variation, resulting in dosing time-dependent differences i...

Genophenotypic Factors and Pharmacogenomics in Adverse Drug Reactions

“…MRP4 protects cells against xenobiotic agents and chemotherapeutic drugs. MRP4 is responsible for the extrusion of oxaliplatin, a platinum-based chemotherapeutic drug, from BMCs and the diurnal expression of MRP4 in BMCs is associated with the dosing time-dependent changes in oxaliplatin-induced myelotoxicity [135].…”

Targeting the Copper Transport System to Improve Treatment Efficacies of Platinum-Containing Drugs in Cancer Chemotherapy

“…Multiple transporters have been reported for oxaliplatin, i.e., the organic cation transporter system (SLC22A), including OCT2 (SLC22A2) [13] and OCT3 (SLC22A3) [14], organic cation/carnitine transporters OCTNs (OCTN1/OCTN2) [15], and multidrug resistance protein 4 (MRP4) [16]. OCTs are a group of poly-specific transporters for subtracts typically of positively charged or zwitterions at physiological pH conditions, e.g., organic amines choline, neurotransmitters dopamine and serotonin, and vitamin B (thiamine) [17].…”

Dosing Time-Dependent Difference in the Suppressive Effect of Empagliflozin on the Development of Mechanical Pain Hypersensitivity in Diabetic Mice

“…Humans generally consume food during the day, so it is thought to be more effective to administer SGLT2 inhibitors before the elevation of blood glucose levels. However, the efficacy and adverse effects of many drugs vary with dosing time and are associated with 24-hour rhythms of various biological processes under the control of the circadian clock (Kato et al, 2020;Omata et al, 2021;Yasukochi et al, 2021). A chronopharmacological strategy can enhance the effects of drugs and lead to the prevention of disease complications.…”