Evaluation of the combined effects of citalopram and bromocriptine in the Caco-2 human colorectal adenocarcinoma cell line

Drug transporters mediate the pharmacological effects of drugs, which are characterized by processes of absorption, distribution, metabolism and elimination. Drug transporters are associated with drug interactions, therapeutic efficacy and drug toxicity. They play a role in intracellular drug accumulation. P-glycoprotein (P-gp) is the efflux transporter. It causes the development of multi-drug resistance (MDR). Citalopram, an antidepressant, increases serotonergic neurotransmission. Bromocriptine is a dopamine receptor agonist. It is a semi-synthetic ergot alkaloid derivative. It is used in the treatment of Parkinson's disease, hyperprolactinemia, Type 2 diabetes, female infertility, acromegaly and Cushing's syndrome. It has been stated that bromocriptine inhibits P-gp function, and citalopram is a substrate of P-gp. There is a possibility of drug interaction when these drugs are used together. Caco-2 is the human colon adenocarcinoma cell line. It is used to study of the drug interaction mechanism in the intestine. In our study on the Caco-2 cell model, the cytotoxic effects of citalopram and bromocriptine separately and combined, dose-dependent (0.625- 5 µM) and time-dependent (24, 48, 72 hours) were determined. After 72 hours, the viability of cells treated with 5μM bromocriptine was significantly reduced (p<0.05). After 72 hours, the viability of cells treated with 2.5 μM and 5 μM citalopram decreased significantly (p<0.01 and p<0.0001, respectively). After 48 hours, the combination of 5 μM bromocriptine and 5μM citalopram significantly reduced cell viability (p<0.05). After 72 hours, 5μM bromocriptine- 5μM citalopram combination (p<0.0001) and 2.5 μM bromocriptine- 2.5 μM citalopram combination (p<0.0001) significantly decreased cell viability. We evaluated the drug interaction coefficients of these two drug combinations. We found that it has synergistic, additive and antagonistic effects at different doses and times. The effect of these drugs on P-gp activity when administered separately or in combination was determined by 3 different protocols. It was observed that they significantly reduced P-gp activity in the 1st and 2nd protocols when applied separately and in combination. In protocol 3, bromocriptine did not significantly affect P-gp activity, while citalopram (p<0.0001) and bromocriptine/citalopram combination (p<0.0001) significantly decreased it. Bromocriptine (p<0.01), citalopram (p<0.0001), bromocriptine/citaloptam combination (p<0.0001) significantly decreased mitochondrial mass. In conclusion, this study will shed light on future studies.