Pharmacokinetics of atropine in dogs after i.m. injection with newly developed dry/wet combination autoinjectors containing HI 6 or HLö 7.

Abstract

To cope with the rapid onset of the life-threatening cholinergic crisis after poisoning with organophosphorus compounds, atropine-oxime preparations should be available in autoinjectors allowing i.m. administration also in the absence of a physician. Such a scenario is conceivable in the battlefield, when nerve agents are disseminated, and can no longer be excluded in civilian areas, as demonstrated most recently in Tokyo. In addition, autoinjectors may be of value in agriculture when medical care is remote. The use of second generation oximes with broad antidotal spectrum, e.g., HI 6 (1-(((4-(aminocarbonyl)pyridinio)methoxy)methyl)-2-((hydr oxyimino)methyl) pyridinium dichloride monohydrate; CAS 34433-31-3) and HLö 7 (1-(((4-(aminocarbonyl)pyridinio)methoxy)methyl) 2,4-bis((hydroxyimino)methyl) pyridinium dimethanesulfonate; CAS 145613-73-6) is only possible in dry/wet autoinjectors because their stability is limited in concentrated solution. To detect a possible delay in atropine absorption by the two oximes, the pharmacokinetics of atropine after "autoinjection" in beagle dogs were determined. Commercially available autoinjectors from two manufacturers [STI International Ltd (BJ) and Astra Tech (AT)] were filled with atropine sulfate, either alone (2 mg) or in combination with HI 6 (500 mg) and HLö 7 (200 mg), respectively, and injected according to a complete cross-over design. Atropine concentration was determined as l-hyoscyamine equivalents in a radioreceptor assay (RRA). In the range of 0.1-6.9 ng/ml, atropine sulfate displaced [N-methyl-3H]-scopolamine methyl chloride ([3H]NMS) competitively from rat cerebral cortex membranes. At 200 pmol/l [3H]NMS, IC50 was 1.4 +/- 0.1 x 10(-9) M atropine (CV = 8.1%). The intra-assay deviation was about 6%; day-to-day deviation in determination of 1 nM (0.695 ng/ml) atropine was 2.6% (CV = 5.2%). AT autoinjectors containing HI 6 delivered only 1.81 mg atropine sulfate while 2.14 mg was released by the other injectors. According to the manufacturer, the reduced delivery was caused by a defective Teflon-coated O-ring as detected later on in the batch used. To allow comparison of the bioavailability of atropine from various autoinjectors, the AUCs were normalized to a constant dose. The atropine absorption half-time (7 min) was not affected either by the autoinjector type or by the combination with oximes. The other pharmacokinetic data likewise did not reveal any differences between the groups. Maximal plasma concentration was 33 ng ml-1, elimination half-life 52 min, Vapp 3.2 l kg-1 and Clpl 44 ml min-1 kg-1. The relatively high clearance of l-hyoscyamine is discussed.