Association of ABCB1 genotypes with paclitaxel-mediated peripheral neuropathy and neutropenia.
Here, we evaluated the relationships between ABCB1 (P-glycoprotein, MDR1) polymorphisms and paclitaxel (Taxol)-induced toxicity and pharmacokinetics. Twenty-six patients were assessable for pharmacogenetics and pharmacokinetics, 22 for neurotoxicity and 18 for myelotoxicity. Patients carrying two reference alleles for the ABCB1 3435C>T polymorphism trended toward a reduced risk to develop neuropathy as compared to patients carrying at least one variant allele (P=0.09). Additionally, patients who were homozygous variant at the 2677 and 3435 loci had a significantly greater percent decrease in absolute neutrophil count at nadir (P=0.02). Neither polymorphism correlated with paclitaxel pharmacokinetics. This pilot study suggests that paclitaxel-induced neuropathy and neutropenia might be linked to inherited variants of ABCB1 through a mechanism that is unrelated to altered plasma pharmacokinetics.
Sissung
Tristan M
TM
Clinical Pharmacology Research Core, National Cancer Institute, 9000 Rockville Pike, Building 10, Room 5A01, Bethesda, MD 20892, USA.
Mross
Klaus
K
Steinberg
Seth M
SM
Behringer
Dirk
D
Figg
William D
WD
Sparreboom
Alex
A
Mielke
Stephan
S
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects*; D005838:Genotype; D006801:Humans; D009503:Neutropenia / Q000139:chemically induced* / Q000235:genetics; D027361:Organic Anion Transporters / Q000235:genetics*; D017239:Paclitaxel / Q000009:adverse effects*; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000235:genetics; D011110:Polymorphism, Genetic / Q000235:genetics*
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D027361:Organic Anion Transporters; D017239:Paclitaxel