effect occurs in humans has yet to be evaluated, but the data suggest interactions between carbaryl and compounds that act via the AhR and between carbaryl and compounds that are metabolized by AhR-induced enzymes.
Carbaryl interacts with cimetidine (Tagamet®), a drug that blocks histamine-induced acid production in the stomach and is used to treat indigestion, acid reflux, heartburn, ulcers, and Zollinger-Ellison syndrome (Ward et al., 1988). May and colleagues (1992) investigated acetylcholinesterase activity in human red cells isolated 1 h after oral administration of carbaryl (at 1 mg/kg) to four healthy people who were taking or not taking cimetidine (at 300 mg every 8 h for 3 days). The results indicate additive effects of high concentrations of cimetidine and carbaryl on the inhibition of red-cell acetylcholinesterase, but no enhanced inhibition was seen at a therapeutically relevant concentration of cimetidine (10 µg/mL). Cotreatment with cimetidine doubled the peak plasma carbaryl concentrations and reduced clearance; carbaryl half-life was unchanged. Maximal inhibition of red-cell acetylcholinesterase activity was statistically significantly reduced. The concentration of carbaryl required to produce 20% inhibition was increased to about 0.5 µg/mL from 0.02 µg/mL. Those findings suggest that carbaryl is metabolized to bioactive metabolites by enzymes that cimetidine inhibits (May et al., 1992).
Mice pretreated with the liver microsomal-enzyme inducer phenobarbital were less susceptible to carbaryl toxicity; those treated with the inhibitor SKF525A demonstrated increased susceptibility (Neskovic et al., 1978). Other studies reported increased toxicity of carbaryl after pretreatment with reserpine or chlordiazepoxide and decreased toxicity after pretreatment with chlorpromazine or meprobamate (Weiss and Orzel, 1967). Tremor induced by carbaryl was substantially reduced by pretreatment with L-dopa and exacerbated by haloperidol; this suggests central catecholaminergic-dopaminergic mechanisms associated with tremor (Ray and Poddar, 1985). Pretreatment of rats with methylmercury hydroxide or chlordane accelerated the urinary excretion of carbaryl (Lucier et al., 1972).
Carpenter and colleagues (1961) reported that the effects of carbaryl were not altered by coadministration of other organophosphorous or other noncarbamate insecticides. However, Lechner and Abdel-Rahman (1986) reported that coadministration of malathion and carbaryl altered pharmacokinetic properties of both insecticides and delayed the elimination of 14C-labeled carbaryl from the plasma of rats. Coadministration of acute equitoxic oral doses of other compounds—such as diphenyl, o-diphenyl, piperonyl butoxide, and thiabendazole—potentiated the effects of carbaryl in mice (Isshiki et al., 1983). Abu-Qare and Abou-Donia (2001) reported that combined exposures to the organophosphate chemical-warfare agent sarin (intramuscular) and the carbamate pyridostigmine bromide (oral) increased concentrations of 3-nitrotyrosine and 8-hydroxy-2-deoxyguanosine, biomarkers of oxidative stress. They also reported decreases in plasma butyrylcholinesterase activity and brain neurotoxic target esterase in hens after combined exposures to pyridostigmine (gavage), DEET (subcutaneous), and chlorpyrifos (subcutaneous) (Abou-Donia et al., 1996) and suggested the possibility that carbamates interact with other neurotoxic pesticides. In another study, however, dermal exposures to DEET did not influence absorption or dermal disposition of carbaryl (Baynes et al., 1997).