Formulation-dependent toxicokinetics explains differences in the GI absorption, bioavailability and acute neurotoxicity of deltamethrin in rats

The acute neurotoxicity of pyrethroid insecticides varies markedly with the dosage vehicle employed. The objective of the present study was to assess the influence of two common vehicles on the bioavailability and toxicokinetics (TK) of a representative pyrethroid insecticide, deltamethrin (DLM), to determine whether the vehicles influence toxic potency by modifying the chemical's TK. Adult, male Sprague–Dawley rats were administered DLM iv or po, either by dissolving it in glycerol formal (GF) or by suspending it in Alkamuls® (AL). Groups of rats received 10 mg DLM/kg by gavage in each vehicle, as well as 2 mg/kg in GF or 10 mg/kg in AL by iv injection. Serial blood samples were collected over 96 h and analyzed for their DLM content by HPLC. In a second experiment, plasma, brain, fat, liver and lung DLM concentrations were measured 2 h after giving 10 mg DLM/kg orally in GF or AL. In a third experiment rats received 2 or 10 mg DLM/kg iv in AL or 2 mg DLM/kg iv in GF. Lung DLM content was determined 15 min post injection. DLM particle size in both formulations was measured under a phase contrast microscope. DLM appeared to be completely dissolved in GF, while particle size ranged from <5 to >50 μm in AL. The bioavailability of DLM in the aqueous AL suspension was ∼9-fold lower than in GF (1.7% versus 15%). Blood Cmax (0.95 ± 0.27 versus 0.09 ± 0.01 μg/ml) and AUC048h (5.49 ± 0.22 versus 0.61 ± 0.14 μg·h/ml) were markedly higher in the GF gavage group. Tissue DLM levels were also significantly higher in the GF animals at 2 h. The 10 mg/kg po and 2 mg/kg iv doses of DLM in GF produced moderate salivation and slight tremors. Rats receiving the insecticide in AL were asymptomatic. IV injection of the AL suspension resulted in trapping of much of the dose in the pulmonary capillaries. As anticipated, the injected suspension had a longer half-life and slower clearance than did the GF formulation. In summary, limited dissolution of the highly lipophilic DLM particles in the AL suspension severely limited DLM's GI absorption, bioavailability, target organ deposition and acute neurotoxic potency.