Vincristine pharmacokinetics

Ince P, Elliott K, Appleton DR, et al. Modulation by verapamil of vincristine pharmacokinetics and sensitivity to metaphase arrest of the normal rat colon in organ culture. Biochem Pharmacol 1991 41(8) 1217-1225. 

Vinblastine is another vesicant vinca alkaloid that causes myelo-suppression and less neurotoxicity than vincristine. The pharmacokinetics of vinblastine are best described by a three-compartment model, with an a half-life of 25 minutes, a 3 half-life of 53 minutes, and a terminal half-life of 19 to 25 hours.12 Vinblastine has shown activity in the treatment of bladder, breast, and kidney cancer, as well as some lymphomas. The doses of vinblastine tend to be higher on a milligram per meter squared basis than vincristine. Nausea and vomiting are minimal with vinblastine. Other side effects include mild alopecia, rash, photosensitivity, and stomatitis. 

The vesicant vinorelbine is structurally similar to vincristine and may cause many of the same side effects as vincristine. While this vesicant is administered intravenously over 6 to 10 minutes, patients should be counseled about neuropathy, ileus, and myelosuppression. The pharmacokinetics of vinorelbine are best described by a three-compartment model, with an a half-life of 2 to 6 minutes, a 3 half-life of 1.9 hours, and a y half-life of 40 hours. Vinorelbine has shown efficacy in the treatment of breast cancer and non-small cell lung cancer. Additional side effects include myelosuppression, paresthesias, and mild nausea and vomiting. 

Webb MS, Harasym TO, Masin D, Bally MB, Mayer LD. Sphingomyelin-cholesterol liposomes significantly enhance the pharmacokinetic and therapeutic properties of vincristine in murine and human tumour models. Br J Cancer 1995 72 896. 

Webb MS, Saxon D, Wong FM, et al. Comparison of different hydrophobic anchors conjugated to poly(ethylene glycol) effects on the pharmacokinetics of liposomal vincristine. Biochim Biophys Acta 1998 1372 272. 

Zhu G, Oto E, Vaage J, et al. The effect of vincristine-polyanion complexes in STEALTH liposomes on pharmacokinetics, toxicity and anti tumor activity. Cancer Chemother Pharmacol 1996 39 138. 

Allen TM, Newman MS, Woodle MC, et al. Pharmacokinetics and anti-tumor activity of vincristine encapsulated in sterically stabilized liposomes. Int J... 

For a number of years following the discovery and initial clinical use of vinblastine and vincristine, there was relatively little definitive information about the pharmacokinetics of these compounds. Pharmacokinetic studies were accomplished typically using radiolabeled drugs and procedures that were of limited value in distinguishing parent drugs from putative metabolites. 

Clinical pharmacokinetic investigations with both vinblastine and vincristine have revealed a triexponential elimination pattern. As for preclinical pharmacokinetic studies, early information was obtained by analysis of samples from patients receiving radiolabeled drug, but more recent investigations make use of radioimmunoassays. It should be noted that radioimmunoassays, while very sensitive in terms of detecting drugs, may also measure structurally related drug metabolites, and some caution is needed in interpretation of pharmacokinetic results obtained from such studies. 

Both vincristine and vinblastine are extensively bound to tissues, and only small amounts of the drug are distributed to the brain or CSE The plasma disappearance of vinblastine and vinorelbine is triphasic. Similar clinical pharmacokinetics have been noted with vincristine and vinorelbine. Biliary excretion is the major route of drug excretion. 

Junping, W, Takayama, K., Nagai, T., and Maitani, Y. (2003) Pharmacokinetics and antitumor effects of vincristine carried by microemulsions composed of PEG-lipid, oleic acid, vitamin E and cholesterol. 

Pharmacokinetics Intravenous injection of vincristine or vinblastine leads to rapid cytotoxic effects and cell destruction. This in turn can cause hyperuricemia due to the oxidation of purines to uric acid. The hyperuricemia is ameliorated by administration of the xanthine oxidase inhibitor, allopurinol (see p. 417). The agents are concentrated and metabolized in the liver and are excreted into bile and feces. Doses must be modified in patients with impaired hepatic function or biliary obstruction. 

Crom WR, deGraaf SS, Synold T, Uges DR, Bloemhoef H, Rivera G, Christensen M, Mahmoud H, Evans WE. Pharmacokinetics of vincristine in children and adolescents with acute lymphocytic leukemia. J Pediatr 1994 125 642-9. 

In a small pharmacokinetic study the clearance of vincristine was 65% greater than in patients who were not taking carbamazepine and the half-life and AUC of vincristine were reduced by 35 and 43% respectively (93). 

Nelson RL, Dyke RW, Root MA. Comparative pharmacokinetics of vindesine, vincristine and vinblastine in patients with cancer. Cancer Treat Rev 1980 7(Suppl l) 17-24. 

Bedikian AY et al (2006) Pharmacokinetics and urinary excretion of vincristine sulfate liposomes injection in metastatic melanoma patients. J CKn Pharmacol 46 727-737... 

The liver extensively metabolizes all three agents, and the conjugates and metabolites are excreted in the bile. Only a small fraction of a dose (<15%) is found in the urine unchanged. In patients with hepatic dysfunction (bilirubin >3 mg/dL), a 75% reduction in dose of any of the vinca alkaloids is advisable. The pharmacokinetics of each of the three drugs are similar, with central and tissue elimination half-lives of 1 and 20 hours for vincristine, 3 and 23 hours for vinblastine, and 1 and 45 hours for vinorelbine, respectively. 

Fedeli L, Colozza M, Boschetti E, Sabalich I, Aristei C, Guerdolini R, Del Favero A, Rossetti R, Tonato M, Rambotti P, Davis S. Pharmacokinetics of vincristine in cancer patients treated with nifedipine. Cancer 1989 64 1805-1811. 

A pharmacokinetic study in patients with non-Hodgkin s lymphoma receiving CHOP (cyclophosphamide, vincristine, prednisone and doxorubicin 37.5 to 50 mg/m ) found that the addition of tamoxifen 480 mg daily for 5 days had no significant effect on the AUC or total clearance of doxorubicin. For the possible additive thromboembolic effect of doxorubicin and tamoxifen, see Antineoplastics + Tamoxifen , p.616. 

Aprepitant had no effect on the pharmacokinetics of a single dose of docetaxeL The activation of cyclophosphamide and thiotepa was slightly lower in patients receiving aprepitant, but this was not clinically relevant. However, because of the possibility of increased toxicity the manufacturer recommends caution with antineoplastics principally metabolised by the cytochrome P450 isoenzyme CYP3A4, particularly irinotecan, and also etoposide, vinorelbine, paclitaxel, ifosfamide, imatinib, vinblastine and vincristine, although there appears to be some limited evidence of safe concurrent use. 

The UK manufacturer of aprepitant recommends caution when it is used with antineoplastics that are metabolised by CYP3A4, particularly irinotecan, because of the possibility of increased toxicity with this drug. They also mention that etoposide, vinoreibine, docetaxel, paclitaxel, ifosfamide, imatinib, vinblastine and vincristine, were given without dosage adjustment for potential interactions, but as this was not a formal interaction study they recommend caution. However, with intravenous docetaxel, it appears that no important changes in pharmacokinetics occur, and therefore dosage adjustments are unlikely to be needed for this drug,... 

Other important research with injectable microemulsions of vincristine (M-VCR) were carried out and its pharmacokinetics, acute toxicity, and antitumor effects were evaluated [41]. The pharmacokinetics, acute toxicity, and antitumor effects of M-VCR were smdied in C57BL/6 mice-bearing mouse murine histocytoma M5076... 

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