title: The decrease of paclitaxel efflux by pretreatment of interferon-γ and tumor necrosis factor-α after intracerebral microinjection.
abstract: Paclitaxel is highly efficacious in the treatment of patients suffering from a broad spectrum of neoplastic diseases. However, its efficacy against malignant glioma is very moderate. Paclitaxel is known to be a substrate for P-glycoprotein (P-gp), so this transporter may be due to insufficient access of paclitaxel to the brain. First, we investigated the brain-to-blood transport of paclitaxel across the blood-brain barrier (BBB) using the brain efflux index method. [(3)H]Paclitaxel was eliminated from rat brain with an efflux transport rate of 1.87×10(-2)±0.16×10(-2)min(-1). The elimination of [(3)H]paclitaxel was inhibited by unlabeled paclitaxel and verapamil, suggesting a carrier-mediated transport process via P-gp. Furthermore, TNF-α and IFN-γ induced significant decrease of paclitaxel efflux 1 and 24h pre-treatment. These results suggest that P-gp efflux function at the BBB is reduced by TNF-α and IFN-γ. Therefore, the distribution of P-gp dependant drugs including paclitaxel in the central nervous system can be modulated by neurological diseases.
authors: College of Pharmacy and Research Center for Cell Fate Control, Sookmyung Women's University, Seoul 140-742, Korea.
authors: Na-Young
authors: NY
authors: Lee
authors: Young-Sook
authors: YS
authors: Kang
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000502:physiology*; D007276:Injections, Intraventricular; D007371:Interferon-gamma / Q000494:pharmacology*; D008297:Male; D017239:Paclitaxel / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D017239:Paclitaxel