Linked Life Data

8616858

Source:http://linkedlifedata.com/resource/pubmed/id/8616858

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PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
9
pubmed:dateCreated
1996-6-12
pubmed:abstractText
Studies in humans and mice have demonstrated a nonlinear pharmacokinetic behavior of paclitaxel. Because of its poor water solubility, the drug is formulated in a mixture of Cremophor EL and ethanol (1:1, v/v; Taxol). We hypothesized that the substantial amounts of concurrently administered Cremophor EL on the disposition of paclitaxel, female FVB mice received paclitazel by i.v. injection at does levels of 2, 10, and 20 mg/kg by appropriate (standard) dilution of the commercially available formulation of paclitaxel (Taxol) with saline. The drug was also given at 2 mg/kg with supplemental Cremophor EL-ethanol to achieve the same amount of vehicle as by standard administration of 10 mg/kg. Furthermore, paclitaxel formulations in Tween 80-ethanol (1:1, v/v) and dimethylacetamide were tested. Plasma samples were collected between 5 min and 48 h, and tissue specimens were sampled at 1, 4, and 8 h after drug administration. Paclitaxel and metabolites were quantified by high-performance liquid chromatography. Cremophor EL levels were determined by a novel high-performance liquid chromatography procedure. For comparative reasons, Cremophor EL was also assayed in plasma samples from three patients receiving a 3-h i.v. infusion of 175 mg/m2 of paclitaxel. A marked nonlinear pharmacokinetic behavior of paclitaxel was observed when the drug was formulated in Cremophor EL-ethanol. The clearance of 2.37 L/h/kg at 2 mg/kg was reduced to 0.33 and 0.15 L/h/kg at 10 and 20 mg/kg, respectively. When 2 mg/kg were given with an amount of Cremophor EL-ethanol matching that of the 10-mg/kg dose level, the clearance was 0.56 L/h/kg. If administered at 10 mg/kg in Tween 80-ethanol or at 2 and 10 mg/kg in dimethylacetamide, the clearances were 2.66, 2.57, and 2.62 L/h/kg, respectively. Despite the fact that much higher plasma levels of paclitaxel are reached when given in the Cremophor EL-ethanol formulation, the tissue levels were essentially similar with all tested drug preparations. The Cremophor EL levels in patients were in the same order of magnitude as those observed in mice after administration of 2 and 10 mg/kg. These data demonstrate that Cremophor EL has a profound effect on the pharmacokinetics of paclitaxel im mice. Because Cremophor EL also contributes substantially to the nonlinear pharmacokinetic behavior of paclitaxel observed in humans.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
May
pubmed:issn
0008-5472
pubmed:author
pubmed:issnType
Print
pubmed:day
1
pubmed:volume
56
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
2112-5
pubmed:dateRevised
2010-11-18
pubmed:meshHeading
pubmed:year
1996
pubmed:articleTitle
Nonlinear pharmacokinetics of paclitaxel in mice results from the pharmaceutical vehicle Cremophor EL.
pubmed:affiliation
Department of Clinical Chemistry, Antoni van Leeuwenhoek Huis, the Netherlands Cancer Institute, Amsterdam, The Netherlands.
pubmed:publicationType
Journal Article