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Increased oral bioavailability of paclitaxel by GF120918 in mice through selective modulation of P-glycoprotein
H A Bardelmeijer1, J H Beijnen, K R Brouwer
1Department of Clinical Chemistry, The Netherlands Cancer Institute (Antoni van Leeuwenhoek Huis), Amsterdam.
Abstract:
Previous studies in mice with disrupted mdr1a P-glycoprotein genes have shown that the oral bioavailability of paclitaxel is very low because of the presence of this drug-transporting protein in the intestinal wall. Additional studies with cyclosporin A have shown that this P-glycoprotein-inhibiting agent is able to increase the bioavailability of paclitaxel in mouse models and in patients. However, the potential immune-suppressive side effects of cyclosporin A renders this compound less suitable for chronic use in cancer patients. In this paper we present the results obtained with GF120918, an experimental P-glycoprotein inhibitor, on the oral bioavailability of paclitaxel in both wild-type and mdrlab knockout mice. GF120918 (25 mg/kg) was administered p.o. by gavage 15 min or 2 h before oral or i.v. dosing of paclitaxel, respectively. Paclitaxel plasma levels were quantified by high-performance liquid chromatography. GF120918 increased the plasma values for areas under the concentration-time curve of oral paclitaxel in wild-type mice by 6.6-fold from 408 to 2701 ng x ml(-1) h. Calculated relative to their respective values for area under the concentration-time curve after i.v. administration, GF120918 increased the oral bioavailability of paclitaxel in wild-type mice from 8.5 to 40.2%. The plasma pharmacokinetics of paclitaxel in mdr1ab knockout mice was not altered by GF120918, whereas the pharmacokinetics of paclitaxel in wild-type mice receiving GF120918 became comparable with mdr1ab knockout mice. This result indicates that GF120918 at this dose-level selectively and completely blocks P-glycoprotein in the intestines and does not notably interfere in the elimination of paclitaxel by metabolism or other transporters. On the basis of this result, GF120918 has been selected for additional study in humans.
Insights
GF120918 significantly enhances oral paclitaxel bioavailability in mice by inhibiting P-glycoprotein. This experimental drug offers a promising alternative to cyclosporin A for cancer patients needing improved paclitaxel absorption.
Area of Science:
- Pharmacology
- Drug Discovery
- Cancer Therapeutics
Background:
- Oral paclitaxel bioavailability is limited by intestinal P-glycoprotein.
- Cyclosporin A enhances paclitaxel bioavailability but has immunosuppressive side effects.
- Need for alternative P-glycoprotein inhibitors for cancer therapy.
Purpose of the Study:
- Evaluate GF120918, a novel P-glycoprotein inhibitor, for enhancing oral paclitaxel bioavailability.
- Compare GF120918's efficacy in wild-type and mdr1ab knockout mice.
- Assess GF120918's safety profile regarding paclitaxel metabolism and elimination.
Main Methods:
- Administered GF120918 orally before paclitaxel dosing in wild-type and mdr1ab knockout mice.
- Quantified paclitaxel plasma levels using high-performance liquid chromatography.
- Calculated pharmacokinetic parameters, including area under the concentration-time curve and oral bioavailability.
Main Results:
- GF120918 increased oral paclitaxel bioavailability by 6.6-fold in wild-type mice (8.5% to 40.2%).
- GF120918 did not alter paclitaxel pharmacokinetics in mdr1ab knockout mice.
- Paclitaxel pharmacokinetics in wild-type mice with GF120918 mimicked those in knockout mice, indicating selective intestinal P-glycoprotein inhibition.
Conclusions:
- GF120918 effectively and selectively inhibits intestinal P-glycoprotein, significantly improving oral paclitaxel bioavailability.
- GF120918 demonstrates a favorable safety profile, without interfering with paclitaxel metabolism or elimination.
- GF120918 is a promising candidate for further clinical investigation in cancer patients.