1. Coadministration of lapatinib increases exposure to docetaxel but not doxorubicin in the small intestine of mice.
- Author
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Hudachek SF and Gustafson DL
- Subjects
- ATP Binding Cassette Transporter, Subfamily B, Member 1 metabolism, Animals, Antineoplastic Agents adverse effects, Antineoplastic Agents blood, Antineoplastic Agents metabolism, Antineoplastic Agents pharmacokinetics, Antineoplastic Combined Chemotherapy Protocols adverse effects, Antineoplastic Combined Chemotherapy Protocols blood, Antineoplastic Combined Chemotherapy Protocols metabolism, Breast Neoplasms drug therapy, Breast Neoplasms metabolism, Clinical Trials, Phase I as Topic, Cytochrome P-450 CYP3A metabolism, Docetaxel, Doxorubicin adverse effects, Doxorubicin blood, Doxorubicin metabolism, Drug Interactions, Female, Half-Life, Humans, Intestine, Small metabolism, Lapatinib, Membrane Transport Modulators adverse effects, Membrane Transport Modulators blood, Membrane Transport Modulators metabolism, Membrane Transport Modulators pharmacokinetics, Mice, Mice, Inbred Strains, Neoplasm Metastasis drug therapy, Quinazolines adverse effects, Quinazolines blood, Quinazolines metabolism, Taxoids adverse effects, Taxoids blood, Taxoids metabolism, Tissue Distribution drug effects, Topoisomerase II Inhibitors blood, Topoisomerase II Inhibitors metabolism, Topoisomerase II Inhibitors pharmacokinetics, Tubulin Modulators adverse effects, Tubulin Modulators blood, Tubulin Modulators metabolism, Tubulin Modulators pharmacokinetics, ATP Binding Cassette Transporter, Subfamily B, Member 1 antagonists & inhibitors, Antineoplastic Combined Chemotherapy Protocols pharmacokinetics, Doxorubicin pharmacokinetics, Intestine, Small drug effects, Quinazolines pharmacokinetics, Taxoids pharmacokinetics
- Abstract
Combination therapy is increasingly being utilized for the treatment of metastatic breast cancer. However, coadministration of drugs, particularly agents that are substrates for or inhibitors of p-glycoprotein, can result in increased tissue toxicity. Unfortunately, determination of levels of chemotherapeutics in human tissues is challenging, and plasma drug concentrations are not always indicative of tissue toxicokinetics or toxicodynamics, especially when tissue penetration is altered. The aim of the present work was to determine whether concomitant administration of compounds currently being combined in clinical trials for metastatic breast cancer treatment alters plasma and tissue pharmacokinetics in mice if both agents are p-glycoprotein substrates and/or inhibitors. Accordingly, we investigated the pharmacokinetic interactions of the classic cytotoxics and p-glycoprotein substrates docetaxel and doxorubicin when administered concurrently with the targeted agent and p-glycoprotein inhibitor lapatinib. Our time-course plasma and tissue distribution studies showed that coadministration of lapatinib with doxorubicin did not appreciably alter the pharmacokinetics of this anthracycline in the plasma or six tissues evaluated in mice, presumably because, at doses relevant to human exposure, lapatinib inhibition of p-glycoprotein did not significantly alter doxorubicin transport out of these tissue compartments. However, combining lapatinib with docetaxel significantly increased intestinal exposure to this chemotherapeutic, which has clinical implications for enhancing gastrointestinal toxicity. The significant lapatinib-docetaxel interaction is likely CYP3A4-mediated, suggesting that caution should be exercised when this combination is administered, particularly to patients with compromised CYP3A activity, and recipients should be monitored closely for enhanced toxicity, particularly for adverse effects on the intestine.
- Published
- 2013
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