Toxicologic and pharmacokinetic study of low doses of verapamil combined with doxorubicin.
The effect of a chronic treatment with low oral doses of verapamil, a calcium channel blocker commonly employed in cardiovascular therapy, on doxorubicin toxicity, was evaluated in CD1 mice. Verapamil, administered at a dosage corresponding to a typical cardiovascular posology in humans, significantly increased doxorubicin toxicity. In particular the mortality was significantly higher and earlier and histological analysis revealed an increase in the severity of lesions in the liver, kidney and small bowel of verapamil pretreated animals. The pharmacokinetic profiles revealed that verapamil treated group had higher doxorubicin peak plasma and tissue levels and AUCs. This study shows that verapamil, administered at low doses, dramatically increases doxorubicin toxicity, probably through an interaction between the two drugs, both P-glycoprotein substrates, on the protein expressed in normal tissues, and suggests caution in the use of the calcium channel blocker for cardiovascular pathologies in patients who have to be treated with antineoplastic agents, substrates of P-glycoprotein.
Candussio
Luigi
L
Department of Biomedical Sciences, University of Trieste, Via L. Giorgieri No. 7, I-34100, Trieste, Italy. candussi@univ.trieste.it
Decorti
Giuliana
G
Crivellato
Enrico
E
Granzotto
Marilena
M
Rosati
Anna
A
Giraldi
Tullio
T
Bartoli
Fiora
F
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*; D004347:Drug Interactions; D005260:Female; D008297:Male; D051379:Mice; D009928:Organ Specificity; D014700:Verapamil / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D002121:Calcium Channel Blockers; D004317:Doxorubicin; D014700:Verapamil