In-vitro metabolism of anti-cancer drugs, methods and applications: paclitaxel, docetaxel, tamoxifen and ifosfamide

Crommentuyn, Kristel M. L.; Schellens, Jan H.M.; Berg, J.D. van den; Beijnen, Jos H.

doi:10.1016/s0305-7372(98)90057-3

Cited by 43 publications

(28 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…administered docetaxel in hyperlipidaemic rats could have been due to the significantly decreased CL (Table 2). Because docetaxel has a low hepatic extraction ratio in rats (Crommentuyn et al 1998), its disposition may be susceptible to changes in intrinsic metabolic CL (Wilkinson & Shand 1975). The hypothesis that docetaxel metabolism was decreased in the hyperlipidaemic rats was supported by a lower CL by the hepatic S9 fractions of the hyperlipidaemic rats compared with those of control rats ( Figure 2).…”

Section: Discussionmentioning

confidence: 95%

Effects of experimental hyperlipidaemia on the pharmacokinetics of docetaxel in rats

Lee

2011

Xenobiotica

View full text Add to dashboard Cite

Hyperlipidaemia correlates with an increased risk of occurrence of various cancers. In this study, the effects of hyperlipidaemia on the pharmacokinetics of docetaxel, a member of the taxane class of anti-cancer drugs, were investigated in rats with experimental hyperlipidaemia; we focused on the alterations in docetaxel metabolism and plasma distribution. Docetaxel (5 mg/kg intravenously (i.v.) and 40 mg/kg per oral (p.o.)) was administered to control rats and rats with poloxamer-407 (P-407)-induced hyperlipidaemia (1 g/kg, intraperitoneally). In vitro studies were conducted on hepatic metabolism in S9 fractions and plasma protein binding using the ultrafiltration method. Hyperlipidaemia dramatically increased the area under the plasma concentration-time curve from time 0 to infinity (AUC(0-∞)) of docetaxel after i.v. (1.86-fold) or p.o. (10.8-fold) administration and decreased total body clearance (0.574-fold) and apparent volume of distribution at steady state (0.615-fold) of docetaxel after i.v. administration. Compared with the control rats, the metabolism of docetaxel by hepatic S9 fractions and the unbound fraction in the plasma in the hyperlipidaemic rats were decreased, i.e., by 20.1 and 79.8%, respectively. In conclusion, the alterations in docetaxel pharmacokinetics in rats with P-407-induced hyperlipidaemia may be due, at least in part, to a decrease in hepatic metabolism and the unbound fraction of docetaxel in the plasma. These findings have potential therapeutic implications for predicting human pharmacokinetic responses to hyperlipidaemia.

show abstract

Section: Discussionmentioning

confidence: 95%

Effects of experimental hyperlipidaemia on the pharmacokinetics of docetaxel in rats

Lee

2011

Xenobiotica

View full text Add to dashboard Cite

show abstract

“…The UGT-A1 phenotype was not associated with increased toxicity but patients homozygous for the (TA) 6 and (TA) 7 phenotype had a slightly better prognosis (36). In our Phase II trial, irinotecan 130 mg/m 2 was administered intravenously over 90 minutes, followed immediately by docetaxel 50 mg/m 2 given over 60 minutes intravenously, every 3 weeks.…”

Section: Discussionmentioning

confidence: 99%

“…Docetaxel shortens the lag time for initiation of polymerization and enhances the rate of tubulin polymerization to form microtubules. This agent is broadly active in a number of tumors, and has been approved for the second-line treatment of breast and non-small cell lung cancer (NSCLC) (2)(3)(4)(5)(6).…”

Section: Introductionmentioning

confidence: 99%

A Phase II NCCTG Study of Irinotecan and Docetaxel in Previously Treated Patients with Non-Small Cell Lung Cancer

Molina

Nikcevich²,

Hillman

et al. 2006

Cancer Investigation

View full text Add to dashboard Cite

show abstract

“…Furthermore, problems may occur for the prediction of in vivo metabolic pathways from in vitro data as a consequence of species differences, in the occurrence of the isozymes, substrate specificities, and rate of metabolism. [40] Despite these difficulties, quantitative in vitro metabolic data can be extrapolated reasonably well to in vivo situations with the application of appropriate pharmacokinetic principles.…”

Section: In Vitro-in Vivo Correlationsmentioning

confidence: 99%

Predicting Pharmacokinetics and Drug Interactions in Patients From in Vitro and in Vivo Models: The Experience With 5,6-Dimethylxanthenone-4-Acetic Acid (Dmxaa), an Anti-Cancer Drug Eliminated Mainly by Conjugation

Zhou

Kestell

Paxton

2002

Drug Metabolism Reviews

View full text Add to dashboard Cite

The novel anti-tumor agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) was developed in the Auckland Cancer Society Research Center. Its pharmacokinetic properties have been investigated using both in vitro and in vivo models, and the resulting data extrapolated to patients. The metabolism of DMXAA has been extensively studied mainly using hepatic microsomes, which indicated that UGT1A9 and UGT2B7-catalyzed glucuronidation on its acetic acid side chain and to a lesser extent CYP1A2-catalyzed hydroxylation of the 6-methyl group are the major metabolic pathways, resulting in DMXAA acyl glucuronide (DMXAA-G) and 6-hydroxymethyl-5-methylxanthenone-4-acetic acid. The predominant metabolite in human urine (up to 60% of total dose) was identified as DMXAA-G, which was chemically reactive, undergoing hydrolysis, intramolecular rearrangement, and covalent binding to plasma proteins. In vivo formation of DMXAA-protein adducts were also observed in cancer patients receiving DMXAA treatment. The comparison of the in vitro human hepatic microsomal metabolism and inhibition of DMXA by UGT and/or CYP substrates with animal species indicated species differences. Renal microsomes from all animal species examined had glucuronidation activity for DMXAA, but lower than the liver. In vitro-in vivo extrapolations based on human microsomal data indicated a 7-fold underestimation of plasma clearance in patients. In contrast, allometric scaling using in vivo data from the mouse, rat, and rabbit predicted a plasma clearance of 3.5 mL/min/kg, similar to that observed in patients (3.7 mL/min/kg). Based on in vitro metabolic inhibition studies, it appears possible to predict the effects on the plasma kinetic profile of DMXAA of drugs such as diclofenac, which are mainly metabolized by UGT2B7. However, it did not appear possible to predict the effect of thalidomide on the pharmacokinetics of DMXAA in patients based on in vitro inhibition and animal studies. These data indicate that preclincial pharmacokinetic studies using both in vitro and in vivo models play an important but different role in predicting pharmacokinetics and drug interactions in patients.

show abstract

In-vitro metabolism of anti-cancer drugs, methods and applications: paclitaxel, docetaxel, tamoxifen and ifosfamide

Cited by 43 publications

References 47 publications

Effects of experimental hyperlipidaemia on the pharmacokinetics of docetaxel in rats

Effects of experimental hyperlipidaemia on the pharmacokinetics of docetaxel in rats

A Phase II NCCTG Study of Irinotecan and Docetaxel in Previously Treated Patients with Non-Small Cell Lung Cancer

Predicting Pharmacokinetics and Drug Interactions in Patients From in Vitro and in Vivo Models: The Experience With 5,6-Dimethylxanthenone-4-Acetic Acid (Dmxaa), an Anti-Cancer Drug Eliminated Mainly by Conjugation

Contact Info

Product

Resources

About