In vivo Microdialysis to Determine the Relative Pharmacokinetics of Drugs.
The purpose of this study was to evaluate a simultaneous microdialysis method in blood and brain striatum to determine the relative pharmacokinetics and metabolism of L-3,4-dihydroxypenylalanine (L-dopa). L-Dopa (250 mumol/kg) was administered to rats with or without the aromatic amino acid decarboxylase (AADC) inhibitor carbidopa (25 mumol/kg) or benserazide (25 or 62.5 mumol/kg). L-Dopa, its metabolites, and AADC inhibitors in dialysates were analyzed by high performance liquid chromatography with an electrochemical detector. A moment analysis was also made to obtain pharmacokinetic parameters. After administration of L-dopa alone, it and its related metabolites were detected in both dialysates of blood and brain striatum. Coadministration of carbidopa (25 mumol/kg) or benserazide (62.5 mumol/kg) significantly enhanced the striatal amount of L-dopa by 8.0 and 6.1 times, respectively. Carbidopa and benserazide also increased striatal amounts of L-dopa metabolites, such as 3,4-dihydroxyphenylacetic acid, homovanillic acid, and 3-methoxy-4-hydroxyphenylethyleneglycol. Inhibition effect of benserazide on an extracerebral decarboxylation of L-dopa to dopamine (DA) was stronger than that of carbidopa. Carbidopa showed a higher striatal level of DA than benserazide. These results suggest a different effect of the two inhibitors on the DA formations in blood and brain striatum, and on the L-dopa transport through the blood-brain barrier (BBB). Thus, microdialysis is an easy and available method for simultaneously assessing the in vivo relative pharmacokinetics and metabolism of drugs in systemic circulation and a target organ.
- [Show abstract] [Hide abstract] ABSTRACT: Simultaneous brain microdialysis in tumour and non-tumour tissues has been used for kinetic determination of the local distribution of an anticancer agent, cisplatin, in rats. Rat brain was implanted with 9L malignant glioma and cisplatin (3.5 mg kg−) was administered as a selective intracarotid infusion for 30 min to rats prepared for brain microdialysis. The amount of platinum in the dialysate collected from tumour and non-tumour brain tissues was determined by atomic absorption spectrophotometry, as representative of cisplatin. Total and free platinum concentrations in plasma were also measured. Free platinum is accumulated preferentially in the tumour tissue and the brain tumour distribution coefficient (the ratio of brain tumour platinum AUC to plasma free platinum AUC, where AUC is the area under the platinum concentration-time curve) was 0.69, although there was little distribution into normal brain tissue. Drug binding to plasma proteins was 65%. It is concluded that simultaneous microdialysis is an easy and available method for assessing in-vivo local pharmacokinetics and distribution of cisplatin in tumour and non-tumour tissues of the brain.0Comments 20Citations
- [Show abstract] [Hide abstract] ABSTRACT: A new microdialysis method (Lipo-MD) using a lipid emulsion as the perfusate instead of Ringer's solution as in conventional microdialysis (MD) was designed. Recovery profiles of the alkylparabens (APBs) dissolved in Ringer' s solution by Lipo-MD were compared with those by MD in vitro. Recovery of APBs in the perfusate in MD decreased with the increasing lipophilicity of APBs, whereas that in Lipo-MD increased. The enhancement of the relative recovery of APBs by Lipo-MD to MD for methyl-, ethyl-, propyl-, and butylparaben were 2.03, 5.24, 77.0, and 390.7, respectively. The utility of Lipo-MD for determination of lipophilic substances to perform pharmacokinetic study was suggested.0Comments 27Citations
- [Show abstract] [Hide abstract] ABSTRACT: As an in vivo technique, microdialysis sampling reflects the composition of the extracellular fluid and can be used in virtually any tissue, organ or biological fluid. Microdialysis has several characteristics that make it a valuable addition to the classical techniques used in pharmacokinetic studies. Probe geometries are described and their suitability for particular target organs is discussed as is tissue response to probe implantation. The application of microdialysis sampling for pharmacokinetic and metabolism studies and its use in target tissues other than the brain have increased over the past decade. This review cites recent examples to illustrate the utility of microdialysis sampling for pharmacokinetic applications.0Comments 108Citations