The effect of increased lipoproteins levels on the disposition of vincristine in rat.
BACKGROUND
Vincristine (VCR), an antineoplastic agent, is a key component in the treatment of acute lymphoblastic leukemia, lymphomas, rhabdomyosarcoma, neuroblastoma, and Wilms' tumor diseases. Recently, high incidence of hyperlipidemia was reported to be associated with allogenic hematopoietic stem cell transplantation and VCR/L-asparaginase therapy. The aim of this study is to test the effects of incremental increase in lipoproteins levels on vincristine disposition in rat.


METHODS
To study VCR pharmacokinetics and protein binding, rats (n = 25) were assigned to three groups, normal lipidemic (NL), intermediate (IHL) and extreme hyperlipidemic (HL). Hyperlipidemia was induced by ip injection of (1 g/Kg) poloxamer 407 in rats. Serial blood samples were collected using the pre-inserted jugular vein cannula for 72 h post VCR (0.15 mg/Kg) i.v. dose. VCR unbound fractions in NL, IHL and HL plasma were determined using ultrafiltration kits.


RESULTS
VCR demonstrated a rapid distribution phase (6-8 h) followed by a slower elimination phase with a mean elimination t½ of ~ 14 h. VCR exhibited moderate binding to plasma proteins ~ 83 %. It showed a relatively small Vc (~0.17 L/Kg) and a larger Vβ (1.53 L/Kg) indicating good tissue distribution. As the lipoproteins levels were increased, no significant changes were noted in VCR unbound fraction, plasma concentration, or volume of distribution indicating low affinity to lipoprotein binding. Induced HL also did not affect VCR elimination where similar VCR AUC0-∞, Cl and elimination phase t½ were reported along the different lipemic groups.


CONCLUSIONS
Incremental increase in lipoprotein levels resulted in no significant effect on VCR disposition as such ALL malignant lymphoma and allogenic hematopoietic stem cell transplantation patients need not to worry about HL-VCR interaction. Whether, HL can potentiate another drug-drug or drug-disease interaction involving VCR warrants further studying and monitoring to ensure therapeutic safety and efficiency.
Pharmaceutical Analytical Chemistry Department, Faculty of Pharmacy, Alexandria University, 1 El Khartoum Square, Alexandria, 21521, Egypt.
Hadeel A
HA
Khalil
Pharmaceutical Analytical Chemistry Department, Faculty of Pharmacy, Alexandria University, 1 El Khartoum Square, Alexandria, 21521, Egypt.
Tarek S
TS
Belal
Department of Pharmacology & Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, 21521, Egypt.|Faculty of Medicine, the American University of Beirut, Lebanon, Alexandria, Egypt.
Ahmed F
AF
El-Yazbi
Pharmaceutical Analytical Chemistry Department, Faculty of Pharmacy, Alexandria University, 1 El Khartoum Square, Alexandria, 21521, Egypt. dr.daliahamdy@gmail.com.
Dalia A
DA
Hamdy
D000818:Animals; D001798:Blood Proteins / Q000187:drug effects / Q000378:metabolism; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects; D006801:Humans; D006949:Hyperlipidemias / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy*; D008074:Lipoproteins / Q000097:blood*; D020442:Poloxamer / Q000633:toxicity; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding; D051381:Rats; D014750:Vincristine / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics
D001798:Blood Proteins; D008074:Lipoproteins; D020442:Poloxamer; D014750:Vincristine
Acute lymphoblastic leukemia; Hyperlipidemia; Neurotoxicity; Pharmacokinetics; Unbound fraction