Interactive alterations of arsenic and malathion in the disposition kinetics of pefloxacin.

Assessment of deleterious effects produced by concurrent exposure to commonly encountered chemicals is of great concern to find out toxicological consequences arising as a result of their interactions and for a more comprehensive management of chemical-induced untoward effects. The naturally occurring heavy metal arsenic is present in food and water. Malathion is one of the most widely used pesticides in agriculture and public health practices worldwide. Humans, animals, and birds are exposed to these chemicals through environmental processes. Since arsenic and malathion are shown to exert an inhibitory effect on cytochrome P450 activities, their continuous exposure may alter the disposition kinetics of drugs that are predominantly metabolized hepatically. The current study was undertaken to evaluate the impact of subchronic exposure of arsenic, malathion, and their combination on the disposition kinetics of widely used fluoroquinolone antimicrobial pefloxacin in chickens. Broiler chickens were exposed to either arsenic (50 ppm), malathion (500 ppm), or arsenic (50 ppm) plus malathion (500 ppm). Arsenic and malathion were given in drinking water and feed, respectively. Following 28 days of exposure, all birds received a single oral dose of pefloxacin (10 mg/kg) and the plasma concentrations and the disposition kinetic parameters of the drug were determined. In the birds not exposed to arsenic and/or malathion, the elimination half-life (t(1/2beta)), area under the plasma concentration-time curve (AUC), maximum plasma drug concentration (C(max)), mean residence time (MRT), and bioavailability of pefloxacin were 8.46 +/- 0.24 h, 39.06 +/- 1.13 microg.h.ml(-1), 2.69 +/- 0.19 microg.ml(-1), 12.29 +/- 0.48 h, and 60.52 +/- 1.74%, respectively. Exposure to arsenic was associated with a significant increase in C(max) (4.28 +/- 0.45 microg.ml(-1)) and a nonsignificant increase in the values of AUC (48.96 +/- 2.55 microg.h.ml(-1)) and bioavailability (74.55 +/- 3.8 %) of pefloxacin. The values of AUC (51.62 +/- 4.76 microg.h.ml(-1)), t(1/2beta) (12.57 +/- 1.26 h), MRT (19.94 +/- 1.99 h), and bioavailability (78.59 +/- 7.25 %) of pefloxacin were significantly increased in malathion-exposed birds. Concomitant exposure to arsenic and malathion did not affect the disposition kinetic variables of pefloxacin. The study shows that subchronic malathion exposure significantly alters the elimination kinetics of pefloxacin. Following concurrent exposure, arsenic nullifies the malathion-induced changes in disposition kinetics of pefloxacin by possibly diminishing the cytochrome P450-catalyzed bioactivation of malathion.