Interactions of pesticides with membrane drug transporters: implications for toxicokinetics and toxicity

Abstract

Drug transporters are now recognized as major actors of pharmacokinetics. They are also likely implicated in toxicokinetics and toxicology of environmental pollutants, notably pesticides, to which humans are widely exposed and which are known to exert various deleterious effects toward health. Interactions of pesticides with drug transporters are therefore important to consider. Areas covered: This review provides an overview of the interactions of pesticides with membrane drug transporters, i.e. inhibition of their activity, regulation of their expression, and handling of pesticides. Consequences for toxicokinetics and toxicity of pesticides are additionally summarized and discussed. Expert opinion: Some pesticides belonging to several chemical classes, such as organochlorine, pyrethroid, and organophosphorus pesticides, have been demonstrated to interact with various uptake and efflux drug transporters, including the efflux pump P-glycoprotein (P-gp) and the uptake organic cation transporters (OCTs). This provides proof of the concept that pesticide-transporter relationships merit attention. More extensive and systematic characterization of pesticide-transporter relationships, possibly through the use of in silico methods, is however likely required. In addition, consideration of transporter polymorphisms, pesticide mixture effects, and realistic pesticide concentrations reached in humans may help better define the in vivo relevance of pesticide-transporter interactions in terms of toxicokinetics and toxicity.

Implication of human drug transporters to toxicokinetics and toxicity of pesticides

“…It thus only represents a relatively small fraction of the total number of pesticides used in the world (more than 1000 (https://www.who.int/topics/pesticides/en/)). The same conclusion applies to other ABC transporters, for which the number of available data regarding effects of pesticides towards their activity is even much lower than that for P‐gp . For some ABC transporters like MRP3, MRP4, MRP5, and BSEP, there are no or only very limited data with respect to agrochemicals, although some of them are considered emerging transporters of clinical importance …”

“…Allethrin and tetramethrin IC 50 values for SLC transporters are from 2.6 μM (for OCT1 inhibition by allethrin) to 77.6 μM (for OAT3 inhibition by tetramethrin), and IC 50 of the neonicotinoid thiacloprid towards OAT3 and OCT2 activities are in the 20–60 μM range . Such concentrations are at least one order of magnitude higher than human plasma concentrations of most pesticides occurring in response to environmental or occupational exposures, which are commonly around the 1 nM to 0.5 μM range . Human concentrations may be even lower for the unbound pesticide fraction, which is the only active one needing consideration.…”

“…Various pesticides block the activity of ABC transporters (See Table S1). Among these ABC transporters, P‐gp is the one for which the highest number of inhibiting pesticides has been reported; at least 20 to 30 pesticides decrease P‐gp‐mediated transport or P‐gp ATPase activity in in vitro models . The total number of pesticides tested against P‐gp activity is, however, rather low, i.e.…”

“…Besides drugs, environmental chemicals, including agrochemicals, interact with drug transporters, as already reviewed . Various pesticides thus inhibit the activity of human transporters and/or are substrates . Moreover, some pesticides regulate the expression of transporters .…”

Neonicotinoid pesticides poorly interact with human drug transporters

“…Drugs are not only substrates for these transporters but may also act as inhibitors, which may cause drug‐drug interactions through altered pharmacokinetics of coadministrated drugs, or adverse effects through impaired transport of endogenous substrates . Besides drugs, environmental pollutants, including pesticides, interact with drug transporters, thus underlining interest in studying potential transporter‐chemical interactions in an extensive and detailed manner . Some pyrethroid insecticides, organophosphorus compounds or organochlorine pesticides thus inhibit activity of ABC and/or SLC drug transporters, whereas other pesticides, like the insecticide methoxychlor or the herbicide 2,4‐dichlorophenoxyacetic acid are substrates for transporters.…”