Age-related differences in vincristine toxicity and biodistribution in wild-type and transporter-deficient mice.
The impact of mouse multidrug resistance genes mdrla/b and mrpl on age-related differences in the toxicity and biodistribution of vincristine (VCR) was evaluated in wild-type, mrpl(-/-), mdrla/b(-/-), and combined mdrla/b(-/-), mrpl(-/-) weanling and adult mice given a single IP dose of VCR ranging from 0.0625 to 6 mg/kg. Weanling mice of all four genotypes were more sensitive than adult animals as determined by survival rate, average time of death, and pathologic findings. Wild-type animals were the least sensitive and combined mdrla/b(-/-), mrpl(-/-) mice the most sensitive to VCR toxicity. Mdrla/b(-/-) and mrpl(-/-) genotypes exhibited intermediate sensitivities, with mdrla/b(-/-) mice being more sensitive than mrpl(-/-) animals to the vinca alkaloid. Administration of [3H]VCR to wild-type and mdrla/b(-/-), mrpl(-/-) animals revealed relatively greater accumulation of radioactive VCR equivalents in weanlings over adults in several tissues, with weanling mdrla/b(-/-), mrpl(-/-) lung and heart exhibiting the greatest enhanced accumulation of 26- and 15-fold over adults, respectively. A similar cardiopulmonary differential accumulation of VCR was not observed in wild-type weanlings to adults. Semiquantitative RT-PCR expression analyses of ABC transporter genes in weanling and adult tissues of wild-type and combined mdrla/b(-/-), mrpl(-/-) mice did not reveal major age-related differences in these ABC transporters that would explain the relatively greater toxicity observed in weanling mice. However, the greater cardiopulmonary accumulation of VCR equivalents seen in the combined mdrla/b(-/-), mrpl(-/-) weanlings over that of adults underscores the potential for unique organ and age-related toxicities of this agent in the setting of transporter deficiency.
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA.
Toshinari
T
Muramatsu
Dennis R
DR
Johnson
Rick A
RA
Finch
Linda K
LK
Johnson
Janine J
JJ
Leffert
Z Ping
ZP
Lin
Giuseppe
G
Pizzorno
Alan C
AC
Sartorelli
D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000502:physiology; D000367:Age Factors; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics* / Q000633:toxicity*; D005260:Female; D019450:Genes, MDR / Q000235:genetics*; D005838:Genotype; D008297:Male; D051379:Mice; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014750:Vincristine / Q000493:pharmacokinetics* / Q000633:toxicity*
D018528:ATP-Binding Cassette Transporters; D000972:Antineoplastic Agents, Phytogenic; D014750:Vincristine