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 10mg DLM/kg by gavage in each vehicle, as well as 2 mg/kg in GF or 10mg/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 2h after giving 10mg DLM/kg orally in GF or AL. In a third experiment rats received 2 or 10mg DLM/kg iv in AL or 2mg 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 microm in AL. The bioavailability of DLM in the aqueous AL suspension was approximately 9-fold lower than in GF (1.7% versus 15%). Blood C(max) (0.95+/-0.27 versus 0.09+/-0.01 microg/ml) and AUC(0)(48h) (5.49+/-0.22 versus 0.61+/-0.14 microg.h/ml) were markedly higher in the GF gavage group. Tissue DLM levels were also significantly higher in the GF animals at 2h. The 10mg/kg po and 2mg/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.
Kim
Kyu-Bong
KB
Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, GA 30605, USA.
Anand
Sathanandam S
SS
Muralidhara
Srinivasa
S
Kim
Hyo J
HJ
Bruckner
James V
JV
D000208:Acute Disease; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical; D006207:Half-Life; D007306:Insecticides / Q000737:chemistry / Q000493:pharmacokinetics* / Q000633:toxicity*; D007408:Intestinal Absorption / Q000502:physiology; D008297:Male; D020258:Neurotoxicity Syndromes / Q000503:physiopathology*; D009570:Nitriles / Q000737:chemistry / Q000493:pharmacokinetics* / Q000633:toxicity*; D010316:Particle Size; D011722:Pyrethrins / Q000737:chemistry / Q000493:pharmacokinetics* / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley
D007306:Insecticides; D009570:Nitriles; D011722:Pyrethrins; C017180:decamethrin