Application and significance of microdialysis sampling technology in pharmacokinetic research

Application and significance of microdialysis sampling technology in pharmacokinetic research
The absorption of drugs in animals (Absorption, A), distribution (D), metabolism (Metabolism, M), excretion (Ex-eretion, E) is one of the contents of preclinical pharmacodynamic studies of drugs, and it is a new drug research. A very important part of it. The reliability of the test results directly affects the correct evaluation of its pharmacodynamics, and the factors affecting the test results, besides the unchangeable objective factors such as the differences between species, are the errors introduced by the test means, due to the ADME of the drug in the body. The process is carried out by studying the changes in drug concentration and time in body fluids, and the sampling process is a key link in pharmacokinetic studies. At present, the conventional sampling method is to analyze the sample after the whole blood is taken from the animal blood vessel, or to analyze the tissue after the animal is subjected to homogenization, and microdialysis (MD) is an emerging sampling technique for pharmacokinetic research. Microdialysis technology is developed from the perfusion technique in the early neurochemical laboratory. It is an in vivo sampling technique based on the dialysis principle, that is, the microdialysis probe is implanted at the desired sampling site for cells. A physiological solution (ie, perfusate) with very similar fluid (including electrolyte composition, ionic strength, osmotic pressure, pH) or an improved perfusion solution containing different additives for perfusion, due to the concentration gradient of the substance to be analyzed inside and outside the membrane, analysis The substance diffuses along the concentration gradient, and the test compound is continuously taken into the body (ie, dialysate) by the perfusate. The concentration of the analyte in the dialysate is measured to study the level of the tissue to be tested, thereby achieving continuous living tissue. The purpose of dynamic sampling. In this paper, the recent reports on microdialysis for pharmacokinetic research are reviewed, and the relevant research is provided for reference.
1 single site microdialysis study
Hadwiger et al. studied the pharmacokinetics of racemic isoproterenol (ISP) enantiomers in rat blood. The interval between dialysate collection in the first 10 min after dosing was 1 min, and the interval was 2 min. HPCE-ECD detection and analysis, dihydroxybenzylamine is an internal standard, and methyl-p-cyclodextrin is a chiral regulator, which enables the sample to be well separated. As a result, the elimination half-lives of (1) ISP and (+) ISP were 9.8 ± 2.2 min and 8.8 ± 2.0 min, respectively, and there was no statistical difference between the two. Gunaratna et al. used brain probe microdialysis combined with collecting jugular venous blood to study the pharmacodynamics and pharmacokinetics of olanzapine after intragastric administration. The brain dialysate was collected and half was determined by HPLC/MS. The concentration of nitrazin was measured by HPLC-EC for the determination of brain neurotransmitter dopamine and serotonin. The rat venous catheter was used to periodically collect blood for pharmacokinetic evaluation, and the rats' autonomic activities were also detected. It indicates that olanzapine can increase the level of brain dopamine, and it also shows that the combination of brain probe microdialysis and sample automatic collector can simultaneously obtain information on pharmacokinetics, pharmacodynamics and physiological activities. Lin et al studied the pharmacokinetics of epicatechin in rats. The dialysate was directly analyzed by HPLC-UVD. The results showed that the pharmacokinetic process was consistent with the two-compartment model. Anand et al studied the pharmacokinetics of fluorescein in the vitreous of rabbit eyes. The experimental rabbits were divided into two groups according to whether there was a recovery period after probe implantation. The blood-retinal integrity was determined by measuring the concentration of vitreal protein and fluorescein. Based on the permeation index, the results showed that the concentration of vitreal protein returned to normal 48 h after implantation of the probe, so the recovery time was set at 72 h, and it was suggested that the probe implantation procedure did not compromise the integrity of the blood-retinal, using microdialysis. Sampling techniques established a method for the study of pharmacokinetics in the posterior segment of the eye. Lv et al. In order to avoid the influence of blood flow changes on the probe implanted in the blood vessel and the irreparable clogging caused by the vessel wall on the probe dialysis membrane, the rabbit is used as the test animal in the ear edge. The vein was immersed in the needle, and the rabbit blood was withdrawn by a variable speed peristaltic pump at a rate of 15 txl/min and then passed through a microtube containing a microdialysis probe. The dialyzate was analyzed by a fluorescence spectrophotometer, and the result showed that the ergot was maleated. The pharmacokinetics of neobase is consistent with a one-compartment model.

2 double site microdialysis study
Tsai et al studied the dynamic changes of tetramethylpyrazine in rat striatum and blood. HPLC-UVD directly analyzed dialysate. The result is that the pharmacokinetics of ligustrazine in blood and brain striatum conforms to the two-compartment model and presents The characteristics of distribution and elimination are fast, and the AUC value of ligustrazine in the two parts indicates that the drug has a relatively high blood-brain barrier permeability. The distribution of brain tissue in the brain within 2 hours is more than twice that in the blood, and the improvement center of ligustrazine The ability to act is consistent. Huf et al. simultaneously measured the amount of amphetidine acetate and dopamine in blood and brain tissue, and observed the activity of the rats at the same time, collected cerebral dialysate and vascular dialysate, and directly determined dopamine and piperidine acetate by HPLC-UVD. The content of methyl ester showed that the peak concentration of methylphenidate acetate in blood and brain tissue reached every 20 minutes after administration, and the level of dopamine also reached the highest level at this time point, and gradually returned to normal level after 3 hours. The maximum activity peak was well correlated with the peaks of amphetidine acetate and dopamine, and the increased activity was maintained for about 2.5 hours. Amal et al. simultaneously measured the pharmacokinetics of phentermine, chloramphetamine and its metabolite nor-chloroamphetamine in rat brain and blood. The dialysate was directly derivatized and then HPLC. As determined by FL analysis, the results indicate chloramphetamine, n/ or nor. Chloramphetamine significantly altered the pharmacokinetics of phentermine in blood and brain tissue, but did not affect the latter's protein binding. However, the pharmacokinetics of chlorpromamine in blood and brain tissue is not affected by the combination with phentermine. Wang et al. compared the pharmacokinetics of phenytoin in peripheral blood and cerebrospinal fluid after intravenous administration of phenytoin and phenytoin (prodrug of phenytoin). The results showed that there was no significant difference in pharmacokinetics between the two in rats. In the past, the results of the whole rat brain homogenization method, that is, the intravenous injection of phenytoin and the intravenous injection of phenytoin, the former has a high concentration of brain tissue, which indicates that the data obtained by the whole brain homogenization method can explain the problem. The reliability is worth considering. Ama studied the pharmacokinetics of phenylpropanolamine in rat blood and striatum. Ephedrine was added as an internal standard to dialysate. After pre-column derivatization, it was directly analyzed by HPLC-FL to obtain styrene-acrylic acid. The pharmacokinetics of alkanolamine in rat blood and brain tissue fluids, and by comparing their AUC values ​​in the brain and blood, there was no statistical difference between the two (P>0.05).

3 three-site microdialysis study
Tsai et al. also studied the pharmacokinetics of berberine in blood, liver and bile of rats. The dialysate was analyzed by HPLC-EVD. The curve of the drug showed that berberine reached peak concentration in the liver and bile after 20 ar intravenous administration. The concentration of bile was significantly higher than that in the blood and liver, and the results suggest that berberine may be excreted in the bile. Tsai et al studied the pharmacokinetics of metronidazole in blood, brain and bile of rats. The dialysate was directly analyzed by micro-inner diameter high performance liquid chromatography-UVD (micro-inner column 5 m, 150×1 mm, I.D.). The results indicate that metronidazole can cross the blood-brain barrier and undergo hepatic and gallbladder excretion, and these properties of metronidazole may be independent of p-glycoprotein. Wu et al studied the pharmacokinetics of pyrazinamide in blood, brain tissue and bile of rats. The dialysate was analyzed by HPLC-uV method, and then the HPLC-MS method was used to verify the results of HPLC-uV method. It indicated that the peripheral and central nervous system pyrazinamide had a rapid exchange and equilibrium process. The results also showed that pyrazinamide could pass the blood-brain barrier and undergo hepatobiliary excretion. Tsai studied the distribution and pharmacokinetics of fuel flavonoids in blood, brain and bile of anesthetized rats. The dialysate was HPLC. UVD analysis showed that a small amount of fuel flavonoids could pass through the blood-brain barrier and undergo bile excretion after intravenous injection into rats. The values ​​of AUCbvain/AUCblood and AUCbile/AUCblood were 0.04±0.01 and 1. 85±0.42, combined with p-glycoprotein blocker cyclosporin, the drug did not significantly improve the distribution of brain and bile, the results suggest that the blood dialysis rate of the drug and hepatobiliary excretion are not affected by p-sugar Protein control. Pia et al. performed a pharmacokinetic/pharmacodynamic (PK/PD) study of dopamine (DA) agonists in rats with the psychostimulant cocaine, methylphenidate and two new candidate psychostimulants NS- A and NS-B were studied in the model. The results showed that the NSA component entered the cerebrospinal fluid at a slower rate than the methylphenidate. However, the two components showed similar effects in accelerating the concentration of the peripheral DA. The speed of the NS-B component entering the cerebrospinal fluid showed Faster characteristics The concentration of 40rain in cerebrospinal fluid reached the maximum after administration. However, the DA value remained unchanged. The results showed that the concentration of D in NS-B was twice as slow as that of methylphenidate and NS-A. Three-probe microdialysis was used to study the feasibility of psychostimulant PKPD in rats.

4 four-site microdialysis study
Tseng et al studied the pharmacokinetics of geniposide in rat blood, liver striatum and bile. The dialysate was directly analyzed by HPLC UVD. The results showed that the dialysate of the probe in the striatum of the brain could not be detected. To geniposide, the drug may not pass the blood-brain barrier, and the pharmacokinetic results in the blood indicate that the pharmacokinetics of the drug is positively correlated with the dose in the dose range of 10 to 100 arg/kg at the dose of 10 mg/kg. The AUC value of the drug in the bile is significantly greater than the blood AUC value, suggesting that the drug has hepatobiliary excretion, and found acupuncture and moxibustion (LIV3) and Yanglingquan (GB34) two points, does not affect the drug in the rat blood, liver, bile The pharmacokinetic process. The application of microdialysis sampling technology in pharmacokinetic research is very
Contribute to the development of pharmacokinetic studies in vivo. Through analysis of the literature, it is recognized that the in vivo recovery rate of the probe at the same site is not affected by the concentration, which is a prerequisite for the in vivo component analysis of the sampling technique, in addition to the microdialysis site where the probe is often implanted in the above-mentioned literature, and Reports on kidney microdialysis, cardiac microdialysis, and small intestinal microdialysis. Of course, this sampling technique also has its limitations. The concentration of the drug in the dialysate represents the average concentration of the drug in the sampling interval. The concentration of the dialysate available for analysis is limited within a certain perfusion rate and sampling interval. This puts high demands on analytical methods and requires highly sensitive quantitative analysis methods; in addition, its microdialysis probes are poorly reusable, so their cost
High also limits the scope of its application.

(Source: Chinese herbal Volume 31, No. 6 of Wei Feng ring)

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