The effect of hydroxychloroquine on the pharmacokinetics of the P-glycoprotein substrate talinolol

Hydroxychloroquine (HCQ) is an antimalarial drug used in the treatment of chronic inflammatory diseases and was included in the treatment protocol of Covid-19 for a period of time and was then withdrawn due to side effects and potential drug-drug interactions. P-glycoprotein (P-gp) is an efflux protein that plays an important role in the pharmacokinetics of drugs and drug-drug interactions as it is highly expressed in various tissues. In this study, we investigated the effects of single-dose and repeated-dose HCQ administration on the pharmacokinetics of Talinolol in Wistar Albino rats. In single-dose group, HCQ (25 mg/kg) and Talinolol (20mg/kg) were administered, in repeated-dose group, HCQ (25 mg/kg) was administered for 7 days and was administered with Talinolol (20mg/kg) on the 8th day. Blood samples were taken at 0.5, 1, 2, 4 and 5. hours and plasma levels of Talinolol were determined with validated HPLC method. Repeated-dose liver P-gp protein levels were determined by Western blot. Cmax and area under the curve (AUCtotal) were evaluated. A single dose of HCQ increased the Cmax (0.16±0.09µg/ml vs 0.23±0.1µg/ml;p=0.3095) and AUCtotal (0.54±0.18µg*h/ml vs 0.74±0.19µg*h/ml;p=0.1905) of Talinolol 1.4 times, whereas repeated administration resulted in a decrease in Cmax (0.22±0.04µg/ml vs 0.19±0.06µg/ ml;p=0.8413) and AUCtotal (0.62±0.11µg*h/ml vs 0.53±0.12µg*h/ml;p=0.3095). Repeated administration of HCQ decreased liver P-gp protein levels. It is thought that the different results we obtained from single-dose and repeated-dose HCQ study may be due to the inhibition of other intestinal uptake transporters by HCQ or the upregulation of other transporters resulting from the inhibition of P-gp.