Increasing nerve agent treatment efficacy by P-glycoprotein inhibition.
One of the shortcomings of current treatment of nerve agent poisoning is that not all drugs effectively penetrate the blood-brain barrier (BBB), whereas most nerve agents easily do. P-glycoprotein (Pgp) efflux transporters at the BBB may contribute to this aspect. It was previously shown that Pgp inhibition by tariquidar enhanced the efficacy of nerve agent treatment when administered as a pretreatment. In the present study soman-induced seizures were also substantially prevented when the animals were intravenously treated with tariquidar post-poisoning, in addition to HI-6 and atropine. In these animals, approximately twice as much AChE activity was present in their brain as compared to control rats. The finding that tariquidar did not affect distribution of soman to the brain indicates that the potentiating effects were a result of interactions of Pgp inhibition with drug distribution. In line with this, atropine appeared to be a substrate for Pgp in in vitro studies in a MDR1/MDCK cell model. This indicates that tariquidar might induce brain region specific effects on atropine distribution, which could contribute to the therapeutic efficacy increase found. Furthermore, the therapeutic enhancement by tariquidar was compared to that of the less specific and less potent Pgp inhibitor cyclosporine A. This compound appeared to induce a protective effect similar to tariquidar. In conclusion, treatment with a Pgp inhibitor resulted in enhanced therapeutic efficacy of HI-6 and atropine in a soman-induced seizure model in the rat. The mechanism underlying these effects should be further investigated. To that end, the potentiating effect of nerve agent treatment should be addressed against a broader range of nerve agents, for oximes and atropine separately, and for those at lower doses. In particular when efficacy against more nerve agents is shown, a Pgp inhibitor such as tariquidar might be a valid addition to nerve agent antidotes.
TNO, CBRN Protection, P.O. Box 45, 2280 AA Rijswijk, The Netherlands. Electronic address: Marloes.joosen@tno.nl.
Marloes J A
MJA
Joosen
TNO, CBRN Protection, P.O. Box 45, 2280 AA Rijswijk, The Netherlands.
Stefanie M
SM
Vester
TNO, CBRN Protection, P.O. Box 45, 2280 AA Rijswijk, The Netherlands.
Jouk
J
Hamelink
TNO, CBRN Protection, P.O. Box 45, 2280 AA Rijswijk, The Netherlands.
Steven D
SD
Klaassen
TNO, CBRN Protection, P.O. Box 45, 2280 AA Rijswijk, The Netherlands.
Roland M
RM
van den Berg
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000110:Acetylcholinesterase / Q000097:blood / Q000378:metabolism; D000818:Animals; D001285:Atropine / Q000378:metabolism / Q000627:therapeutic use; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000201:enzymology / Q000378:metabolism; D004285:Dogs; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D000067397:Nerve Agents / Q000506:poisoning*; D010091:Oximes / Q000378:metabolism / Q000627:therapeutic use; D011726:Pyridinium Compounds / Q000378:metabolism / Q000627:therapeutic use; D011804:Quinolines / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D012999:Soman / Q000633:toxicity; D013379:Substrate Specificity
D018435:ATP Binding Cassette Transporter, Subfamily B; D000067397:Nerve Agents; D010091:Oximes; D011726:Pyridinium Compounds; D011804:Quinolines; D001285:Atropine; D012999:Soman; D000110:Acetylcholinesterase; C022870:asoxime chloride; C402343:tariquidar
Atropine; Oxime; Seizures; Soman; Tariquidar; p-Glycoprotein