HPLC-UV bioanalysis method development & therapeutic drug monitoring for 5-fluorouracil nanoformulation in rat plasma and its toxicological and pharmacokinetic applicationAbstract:Aim: Our study included the formulation of 5-fluorouracil nanoformulation and identification of rapid, reactive and vigorous analytical & bioanalytical HPLC-UV method validation and its application upon the pharmacokinetic study and determination of acute toxicological profile of the drug in Sprague Dawley rats.Background: 5-Fluorouracil is an anti-cancerous drug use against many types of cancer. The nanoparticles loaded drug has the ability to overcome the toxicity, low bioavailability, short half-life and extend the efficacy on the cancer cells. The HPLC-UV method used to develop a simple & rapid validation for quantification determination formulated formulation.Methodology: The HPLC-UV method used to validate the analytical method development in the expression of specificity, sensitivity, precision, accuracy & stability and further correlated with pharmacokinetics and toxicological profile of the 5-FU nanoformulation on rat plasma. PLGA (poly-lactic-co-glycolic acid) used as a polymer to hold 5-FU-in a nanoformulation by solvent evaporation. The developed nanoparticles of 5-FU, evaluated on the basis of particles size analysis, shape & surface morphology and further HPLC-UV method have been employed for the validation of analytical & its application over pharmacokinetic data collection.Results: The stable polymeric nanoformulation of 5-FU ranges the size of 137±0.95 to 195±0.96 nm and surface charges lie between 0.26±0.09 to 0.30±0.06 mv. The pharmacokinetics drug profile of 5-FUNPs was collected on the basis of validated HPLC-UV analytical method, highest peak concentration, Cmax 3.25±0.75 mg/L at the highest time point, Tmax 7.21±2.50 hrs and the area under the curve were 8.90±5.0 mg/L-h (AUC 0-96) & 9.50±3.4 mg/L-h (AUC 0-?). The t(1/2) was 21.65±4.45 hrs.Interpretation:Our study concluded that 5-FU polymeric nanoparticles show an informative pharmacokinetic data to correlates with clinical findings, after the formulation of nanoformulation the HPLC-UV spectroscopic analytical method were successfully developed and validated and further applied over pharmacokinetics study. Keywords: 5-fluorouracil, HPLC-UV, nanoparticles, pharmacokinetics, PLGA.Introduction:Chemotherapy in combination with nanotechnology as nano-chemo-therapy provides a wide range of drug formulation perhaps it provides a specific therapy over the cancer region (Bhirde et al., 2009), high efficacy, safety & minimum side effects over the conventional chemotherapy (Ahmad et al., 2017). The unique design of nanoparticles provides a platform for dispensing the cancer drug through specific pathways on cancer cell region with a minimum side effect on normal cells (Jenning et al., 2000). The use of polymeric nanoparticles is providing a controlled release of drug specifically over tumour cell & widely accepted drug delivery system against cancer to diagnosis and drug therapy. Nanoparticles within a drug capsule create a great potential to demonstrated and enhance controlled drug delivery system (Shadab et al 2015). Polymeric nanoparticles with chemotherapeutic drug molecule developed a conjugate/encapsulated carrier system for newer nano-chemotherapy and polymeric-nanoformulation provides a submicron size (1-1000 nm) of colloidal drug particles with multifunctional/multi-component drug system over the cancer treatment. In this drug therapy, the therapeutic agent can be able to encapsulate in this bunch of matrix and get absorbed on the surface. Now’s days nanoparticles are using as drug delivery vehicles with different biodegradable polymers for the enhancement of efficacy, half-life, targeted delivery thereby increase the therapeutic index of particular drug system (Liu et al., 2012). 5-fluorouracil (5-FU) is a chemotherapeutic agent for an anticancer activity, it is an analogue of pyrimidine uracil which occurs naturally (Yishing et al., 2014). Clinical metabolism of 5-FU indicates that the anabolic pathway inhibits in between the methylation reaction of deoxyuridylic acid to thymidylic acid. The pathway of 5FU activity is interfering the DNA formation and so that indirectly its growth and its division and resultant death of cell occur because of thymine deficiency (Bocci et al., 2006). The conventional dosage of 5-FU has the short half-life, less bioavailability, non-specific drug delivery and other many adverse effects. (Nair et al., 2011). In addition with drug delivery to any molecule like 5FU with nanotechnology leads to minimizing their limitation such as short half-life, toxicity, and non-selective action against cell by the unique properties of nanoparticles with nano-size dual/triblock structures (Oh et al., 1999). During the research on the classical antitumor entity 5 FU, the pharmacokinetic profile is needed of the formulated novel polymeric nanoparticles (Matteucci et al., 2006). Our study is mainly focused to develop the polymeric 5-FU nanoparticles and validation of analytical data to collect the complete drug profile of the drug. HPLC-UV (high-performance liquid chromatography-ultraviolet) is very much reliable and classical technique to identify the quantitative analytical method development and validation (Kumar et al., 2014).Material & Method:Chemical & Reagents: 5-Fluorouracil (5-FU) Extra (Cas No. 51.21.9) was obtained from Sigma Aldrich, PLGA, Polyvinyl chloride, Megestrol acetate, Acetonitrile & methanol, Extraction agent ethyl acetate, other chemicals & solvents were of HPLC grade purity.Method of Preparation & Characterization: The polymeric nanoparticles of PLGA were formulated by the using the technique oil-in-water emulsion/solvent evaporation (Levin et al., 2000). For the preparation of 5-fluorouracil (5-FU) at a concentration of 1% (m/v), 10 mg of 5-fluorouracil was dissolved in this solution of MEK (methyl ethyl ketone) 10 ml and myritol (250 mg) and mixed properly called solution-1. PLGA polymer was dissolved in 25 ml of Dichloromethane and further added in solution-1, this mixture was sonicated for 2 min to make a pre-emulsion. This mixer was added to a prepared aqueous solution of PVC surfactant (100 mg in 50 ml) and sonicated for 10 min. This emulsion was concentrated for a volume of 10 ml using rotary evaporator and found the concentration of 5-fluorouracil 1% (m/v) and called 5-fluorouracil nanoparticles (5-FUNPs). This formulation was characterized on the basis of particles size, zeta potential, TEM analysis & In-vitro drug release system.

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