Effect of Repeated Low-Dose Organophosphorothionate Pesticide Exposure on Digoxin Pharmacokinetics in Rats; a Possible Interaction Involving P-Glycoprotein

Abstract

ABSTRACTAside from acute occupational exposure, an important part of the population may be chronically exposed to the trace amounts of organophosphorothionate pesticides (OPTs) via residues in nutrients and drinking water. P-glycoprotein (P-gp) is a transmembrane protein responsible for the efflux of numerous drugs. OPTs were shown to inhibit P-gp function in vitro and increase its expression in vivo. Digoxin is a probe drug for the investigation of P-gp. To evaluate the effect of repeated low-dose OPT exposure on P-gp, commercial formulations of diluted OPT or tap water were administered to female Wistar rats for 8 consecutive days. On the ninth day each group was further divided into two groups and digoxin was administered either intraduodenally (ID) or intravenously (IV). Blood sampling and bile and urine collection were taken during 6 h at various intervals. The peak concentration in serum (Cmax) of digoxin was found to be decreased and the mean absorption time (MAT) was significantly increased in the digoxin OPT group. The mean residence time was significantly elevated in the digoxinID OPT group. The biliary excretion% digoxin was significantly increased in the digoxin OPT group, while the renal excretion% digoxin rose only in the digoxinID OPT group. No significant differences in time to reach Cmax (tmax), area under the plasma concentration-time curve (AUC)0–360, area under the moment curve (AUMC)0–360, and bioavailability (F) were detected. In our study, repeated low-dose OPT exposure reduced the absorption and increased the excretion% digoxin, which may be related to enhanced P-gp expression. However, alterations of digoxin pharmacokinetic parameters did not change the systemic availability of digoxin.