Environmental Toxicology and Pharmacology 24 (2007) 1–4 Effect of subacute methyl parathion administration on th pharmacokinetics and pharmacodynamics of nifedipine in r Ayse Gelal ∗ , Ozlem Eminoglu, Y.Cem Kaplan, Sule Kalkan Dokuz Eylul University Medical Faculty, Department of Pharmacology, Inciralti, 35340 Izmir, Turkey Received 1 August 2006; received in revised form 28 November 2006; accepted 30 November 2006 Available online 9 December 2006 Abstract Families living in agricultural areas may submitted to repeated exposure of methyl parathion (MP) that has been widel insecticide. MP inhibits cytochrome P450 enzymes and has the potential to alter pharmacokinetic profiles of therapeutic in the liver. The aim of the present study is to investigate the possibility that the increased pharmacokinetic and pharmac is due to the inhibition of the metabolism after repeated administration of low doses of MP in rats. Male rats received com diluted MP (1/100 LD 50 or 1/25 LD 50 , n = 6) or tap water (control, n = 5) via gastric gavage (0.5 ml) for 14 days. On the 15th da and jugular vein were cannulated for measurement of cardiovascular parameters and blood sampling, respectively. Nifed 3 mg/kg via the cannula inserted in the duodenum of the rat. Subacute MP administration did not change pharmacokinetic AUC (0–240) , C max , t max , t 1/2 ) and pharmacodynamic (mean arterial pressures and heart rates) parameters of nifedipine. These findings provide exposure of low doses of commercial MP did not affect the elimination of nifedipine which might be due to the lack of inh in rats. © 2006 Elsevier B.V. All rights reserved. Keywords: Methyl parathion; Organophosphate pesticides; Nifedipine; CYP450; Rats 1. Introduction In Turkey,phosphorothioate pesticides, such asmethyl parathion (MP), are in widespread use in agriculture (Tuncok et al., 1995). Families living in agricultural areas may submitted to repeated exposure of organophosphate pesticides. As a result of their extensive and non-judicious use, beside occupational exposure to high doses, there is potential for low-dose exposure of pesticides to a large part of the population due to their pres- ence as residues in food and drinking water. It has been observed that their long-term, low-dose exposure is increasingly linked to human health effects (Gupta, 2004). Parathion is known to inhibit hepatic cytochrome P450 (CYP450) (Murray and Reidy, 1990). In previous in vitro stud- ies, it has been reported that transfer of the thiono-sulfur atom to the CYP450 moiety occurs during phosphorothioate bioac- tivation which consequently results in CYP inactivation in the ∗ Corresponding author. Tel.: +90 232 4123904; fax: +90 232 2599723. E-mail address: ayse.gelal@deu.edu.tr (A. Gelal). liver (Butler and Murray, 1997).It is now apparent thatcer- tain hepatic microsomal CYP450s are especially suscept inactivation during the oxidation of parathion. The const CYP450 enzymes CYP2C11 and CYP3A2 were found to b deactivated in microsomes from rat liver by parathion ( B and Murray, 1993).Otherstudies with human liver micro- somes found similar results in that CYP3A4 was a principal target for parathion-mediated inactivation ( Butler and M 1997). CYP3A4 is responsible for the metabolism of a large n of therapeutic agents and endogenous substrates. This e has been shown to be involved in a significant numberof drug–drug interactions leading to adverse drug reaction toxicity resulting from alterations in activity and express (Dresser et al., 2000). Nifedipine is rapidly and almost completely absorbed the gastrointestinal tract,butundergoes an extensive hepatic first-pass metabolism, resulting in a systemic availability of about 46%. Nifedipine is primarily metabolised in the gu and liver into inactive metabolites by CYP 3A in the hum additional 2C subclass in the rat. 1382-6689/$ – see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.etap.2006.11.010