Vincristine-induced neuropathy in the rat is not modified by drug-drug interactions with the P-glycoprotein inhibitor verapamil.
BACKGROUND
Cancer patients can be exposed to drug interactions during treatment with toxic anticancer drugs. The peripheral nervous system is a target for neurotoxic anticancer drugs. P-glycoprotein is essential for the functional integrity of blood-tissue barriers, and P-glycoprotein inhibition due to possible drug interactions could lead to adverse neurotoxic reactions.


METHODS
In a rat model of vincristine-induced neuropathy, we assessed the consequences of potential drug interactions of vincristine with some P-glycoprotein-inhibiting drugs, chosen because of their potency to increase the incorporation of (99m)Tc-sestamibi in nervous tissue.


RESULTS
Quinidine (30 mg/kg) increased (99m)Tc-sestamibi incorporation in dorsal root ganglia (DRG) but was toxic for rats. Verapamil (30 mg/kg) increased the tracer incorporation in the spinal cord, DRG and sciatic nerve. Combination treatment with the verapamil-vincristine regimen had a tendency to lower weight gain and altered nociceptive thresholds of neuropathic animals.


CONCLUSIONS
Behavioral pain tests did not reveal an increase in vincristine neurotoxicity following combination treatment with verapamil and vincristine. This regimen only led to a slight increase in general toxicity.
Balayssac
David
D
Laboratoire de Toxicologie, Faculté de Pharmacie, Clermont Université, Université d'Auvergne, Clermont-Ferrand, France. dbalayssac@chu-clermontferrand.fr
Cayre
Anne
A
Ling
Bing
B
Maublant
Jean
J
Penault-Llorca
Frederique
F
Eschalier
Alain
A
Coudore
François
F
Authier
Nicolas
N
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004347:Drug Interactions; D008297:Male; D009422:Nervous System Diseases / Q000139:chemically induced*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014700:Verapamil / Q000009:adverse effects; D014750:Vincristine / Q000009:adverse effects*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D014750:Vincristine; D014700:Verapamil