PHARMACOKINETIC EVALUATION OF PHYTOL IN RATS
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Date
2022-10-27
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COLLEGE OF VETERINARY AND ANIMAL SCIENCS, POOKODE, WAYANAD, KERALA VETERINARY AND ANIMAL SCIENCES UNIVERSITY
Abstract
Phytol (3,7,11,15- tetramethylhexadec-2-en-1-ol) is a diterpene and a branched-chain unsaturated acyclic fatty alcohol, abundantly present in nature as a part of the chlorophyll molecule. Phytol is metabolised in the liver into phytanic acid and pristanic acid. Phytol possesses a wide range of bioactivities including antioxidant, cytotoxic, autophagy and apoptosis-inducing, anti-nociceptive, anti-inflammatory, immune-modulating, antimicrobial, antianxiety, and anticonvulsant effects. So far no data is available on the pharmacokinetics of phytol in any animal species. The present study was conducted to investigate the pharmacokinetics of phytol after the oral and intravenous administration and to assess the residual retention of phytol and its metabolites in different organs. A quantifiable GC-MS method was developed for the determination of phytol and its metabolites in rat plasma and different tissues. Single dose of phytol was given orally and intravenously to separate groups of rats at a dose rate of 250 mg/kg and 25 mg/kg respectively. Blood was collected at predetermined time intervals up to 24 h and 168 h post intravenous and oral administration respectively. The blood concentrations were determined and pharmacokinetic analysis were done using PK Solver, version. 2.0. The animals were sacrificed on 7, 14, 21 and 28 days following oral and seven days post intravenous administration and organs were collected for residue analysis of phytol and its metabolites.
Phytol and its metabolites were present in plasma in detectable concentrations at all sampling times after oral and intravenous administration. The plasma concentration of pristanic acid was higher followed by phytanic acid and phytol. Remarkable double peaks for phytol were observed in plasma concentration-time curve following oral administration whereas after intravenous administration the plasma concentration of phytol decreased rapidly in zig-zag manner during the first hour and more slowly thereafter. Pharmacokinetics of orally administered phytol in rats fitted best into a non-compartment model. The absorption of phytol into blood was very rapid with the time to reach maximum concentration in plasma ranges from 2.19 to 4.23 h with 95% confidence interval. The terminal half-life (t1/2), maximum plasma concentration (Cmax) and mean resident time (MRT) were 84.53 h, 1.38 μg/mL, and 117.74 h respectively. The apparent volume of distribution (Vd) and clearance were found to be 1015.03 ± 136.54 mL/g and 9.34 ± 1.25 mL/g/h respectively. Additionally, from six hour onwards it is best fitted into a two compartmental model as evident by the concentration against time curve. Phytol tends to accumulate in the brain, seminal vesicle and small intestine of rats after 28th day post administration. In addition, phytol was also detected in the liver, lung, adrenal gland, stomach, kidney, heart, reproductive organs, caecum and spleen after seventh day of post administration. Phytanic acid was detected in almost all the organs with highest concentration in stomach, small intestine and caecum.
After intravenous administration of phytol, the plasma concentrations of phytol and its metabolites was detected till 24 h. Pharmacokinetics of intravenously administered phytol in rats also fitted best into a non-compartment model. The Cmax, and Tmax were 0.08 ± 0.02 µg/mL and 0.73 ± 0.37 h respectively. The terminal elimination half-life (T1/2) and MRT were 68.32 ± 22.14 h and 98.09 ± 32.05 h respectively. The steady-state volume of distribution (Vdss) and apparent volume of distribution during terminal phase (Vdλ) and clearance were 516.21 ±78.28 mL/g 520.37 ± 76.73 mL/g and 7.28 ± 1.57 mL/g/h respectively. Phytol was detected in the brain, liver, kidney, adrenal gland, seminal vesicle, fat, small intestine and caecum seven days post intravenous administration. Phytanic acid was detected in almost all the tissues. In the fat tissue, the peak area of phytol could not be separated as it merged with areas of other fatty acid components.
In conclusion, it was found that phytol was rapidly absorbed from gastro intestinal tract after oral administration with wider distribution and slow elimination. Phytol possesses all favourable pharmacokinetic parameters for a possible therapeutic agent.