title: Hyperlipidemia Alters the Pharmacokinetics of Posaconazole and Vincristine Upon Co-Administration in Rats.
abstract: OBJECTIVE
  Co-administration of posaconazole (PSZ) and vincristine (VCR) in the treatment of patients with acute lymphoblastic leukemia increases the neurotoxicity of VCR. Our aim is to study the effect of increased lipoprotein levels on the pharmacokinetics of PSZ and VCR upon co-administration in rats.
  
  
  METHODS
  Rats were assigned to three groups, normolipidemic (NL), intermediate hyperlipidemic (IHL), and extreme hyperlipidemic (HL) groups. All rats were administered PSZ orally followed by VCR intravenously 4 h later. For the pharmacokinetic study, serial plasma samples were collected over 96 h and for tissue distribution study; plasma, lung, and liver tissues were collected over 48 h post oral dosing.
  
  
  RESULTS
  Posaconazole showed higher plasma concentrations than VCR at all time points. Co-administration of VCR with PSZ reduced PSZ weight normalized oral clearance, increased PSZ area under the plasma concentration-time curve (AUC) from time zero to infinity, showed higher PSZ liver concentrations, and increased VCR volume of distribution of the central compartment. Upon increasing the lipoprotein levels, PSZ showed higher plasma availability and delayed tissue distribution, whereas VCR had shown a significant decrease in PSZ AUC0-24h, AUC0-tlast, and AUCo-inf(NL = IHL > HL) and a significant increase in the volume of distribution (NL = IHL < HL). Vincristine has shown higher tissue uptake and concentrations.
  
  
  CONCLUSIONS
  Monitoring cholesterol and triglyceride levels in patients with acute lymphoblastic leukemia is advisable to decrease VCR neurological side effect incidences and delay the activity of both PSZ and VCR.
authors.affiliation: Department of Pharmaceutical Analytical Chemistry, Faculty of Pharmacy, Alexandria University, 1 El Khartoum Square, P.O. Box 21521, Alexandria, 21521, Egypt.
authors.forename: Hadeel A
authors.initials: HA
authors.lastname: Khalil
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt.
authors.forename: Mohammed A W
authors.initials: MAW
authors.lastname: ElKhatib
authors.affiliation: Department of Pharmaceutical Analytical Chemistry, Faculty of Pharmacy, Alexandria University, 1 El Khartoum Square, P.O. Box 21521, Alexandria, 21521, Egypt.
authors.forename: Tarek S
authors.initials: TS
authors.lastname: Belal
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt.|Department of Pharmacology and Toxicology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon.
authors.forename: Ahmed F
authors.initials: AF
authors.lastname: El-Yazbi
authors.affiliation: Department of Pharmaceutical Analytical Chemistry, Faculty of Pharmacy, Alexandria University, 1 El Khartoum Square, P.O. Box 21521, Alexandria, 21521, Egypt. dr.daliahamdy@gmail.com.
authors.forename: Dalia A
authors.identifier: http://orcid.org/0000-0002-7427-0180
authors.initials: DA
authors.lastname: Hamdy
mesh_terms: D000818:Animals; D004347:Drug Interactions; D004359:Drug Therapy, Combination / Q000009:adverse effects*; D006949:Hyperlipidemias / Q000139:chemically induced*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution / Q000187:drug effects; D014230:Triazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D014750:Vincristine / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*
chemical_list: D014230:Triazoles; D014750:Vincristine; C101425:posaconazole