Altered pharmacokinetics of vinblastine in Mdr1a P-glycoprotein-deficient Mice.

BACKGROUND

P-glycoprotein (Pgp) is a membrane protein that acts as an extrusion pump for many cytotoxic drugs. Pgp is expressed in normal tissues, and its (over)expression in tumor cells contributes to their drug resistance. Human Pgp is encoded by the MDR1 gene, In mice, two Pgps (encoded by the mdr1a and mdr1b genes) appear to perform the same function as the single human protein. The simultaneous use of cytotoxic drugs and agents that block Pgp function has raised questions of safety, since a blockade of Pgp in normal tissues could alter drug pharmacokinetics and change the spectrum of toxic side effects. Analysis of the consequences of Pgp blockade has been facilitated by the generation of mice with disrupted mdr1a genes [mdr1a(-/-)].

PURPOSE

We studied the plasma pharmaco-kinetics, tissue distribution, and excretion of the cytotoxic drug vinblastine (VBL) and its metabolites in mdr1a (-/-) mice and in wild-type [mdr1a(+/+)] mice.

METHODS

VBL was administered to mice in bolus doses of either 1 or 6 mg/kg body weight by intravenous injection. VBL and its metabolites were quantified in tissue specimens, plasma, feces, and urine by use of high-performance liquid chromatography. Liquid scintillation counting was used to measure radioactivity in specimens from animals that had received [3H]VBL. Pharmacokinetic parameters were calculated by use of noncompartmental methods. Only two-sided P values are reported.

RESULTS

The half-life (t1/2) of VBL during its terminal phase of elimination was longer in mdr1a (-/-) mice than in wild-type mice. The t1/2 values with a 1-mg/kg dose were 3.6 hours +/- 0.3 hour (mean +/- standard error) and 2.1 hours +/- 0.3 hour, respectively (P < .05); with a 6-mg/kg dose, the values were 8.6 hours +/- 1.8 hours and 4.2 hours +/- 0.2 hour, respectively (P = .058). Fecal excretion of nonmetabolized VBL was reduced from 20%-25% of the administered dose (either 1 or 6 mg/kg) in wild-type mice to 9.3% (1-mg/kg dose) or 3.4% (6-mg/kg dose) in mdr1a(-/-) mice (both P < .05); the cumulative urinary excretion of VBL was low (< 6% of the administered dose) and not substantially different in the two types of mice. The metabolism of VBL to hydrophilic compounds, a primary mechanism involved in its elimination, was not altered in mdr1a(-/-) mice. The brains of mdr1a(-/-) mice accumulated substantially more VBL than the brains of wild-type mice. In mdr1a(-/-) mice, a few other tissues, such as the heart and the liver, accumulated increased amounts of VBL, but the relative levels of accumulation were lower than those found in the brain.

CONCLUSIONS

Mice lacking the Pgp encoded by the mdr1a gene exhibit reduced fecal excretion of VBL, leading to a prolonged elimination t1/2 for this drug. Intact mdr1a function appears to protect the brain against high plasma levels of VBL, but most other tissues are not similarly protected.

IMPLICATIONS

Enhanced drug accumulation in nonmalignant tissues after Pgp blockade should be carefully considered in future clinical trials of Pgp modulation.