A phase I study on the reversal of multidrug resistance (MDR) in vivo: nifedipine plus etoposide.
Multidrug resistance (MDR) is one of the mechanisms of resistance to multiple cytotoxic drugs and is mediated by the expression of a membrane pump called the P-glycoprotein. Nifedipine is one of the calcium channel blocking agents which reverses MDR in vitro. Fifteen patients with various malignancies received nifedipine at three dose levels: 40 mg, 60 mg and 80 mg orally twice daily for 6 days. Etoposide was administered intravenously on day 2 in a dose of 150-250 mg m-2 and orally 150-300 mg twice daily on days 3 and 4. Cardiovascular effects of nifedipine were dose limiting and the maximum tolerated dose was 60 mg bid. Mean area under the plasma concentration curve (AUC0-00) and plasma half-life (beta) of nifedipine and its major metabolite MI at the highest dose level were 7.87 microM.h, 7.97 h and 4.97 microM.h, 14.0 h respectively. Nifedipine did not interfere with the pharmacokinetics of etoposide.
Philip
P A
PA
ICRF Clinical Oncology Unit, Churchill Hospital, Oxford, UK.
Joel
S
S
Monkman
S C
SC
Dolega-Ossowski
E
E
Tonkin
K
K
Carmichael
J
J
Idle
J R
JR
Harris
A L
AL
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D004334:Drug Administration Schedule; D004341:Drug Evaluation; D004347:Drug Interactions; D004351:Drug Resistance; D005047:Etoposide / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D009543:Nifedipine / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics
D005047:Etoposide; D009543:Nifedipine