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.
Nakashima
M
M
Department of Hospital Pharmacy, Nagasaki University School of Medicine, Japan.
Zhao
M F
MF
Nakashima
M N
MN
Sakurai
M
M
Sasaki
H
H
Matsuyama
K
K
Ichikawa
M
M
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D000978:Antiparkinson Agents / Q000493:pharmacokinetics*; D001545:Benserazide / Q000493:pharmacokinetics; D001923:Brain Chemistry / Q000187:drug effects; D002230:Carbidopa / Q000493:pharmacokinetics; D002851:Chromatography, High Pressure Liquid; D004298:Dopamine / Q000378:metabolism; D004347:Drug Interactions; D004563:Electrochemistry; D006719:Homovanillic Acid / Q000378:metabolism; D007980:Levodopa / Q000493:pharmacokinetics*; D008297:Male; D008734:Methoxyhydroxyphenylglycol / Q000378:metabolism; D017551:Microdialysis / Q000379:methods*; D017072:Neostriatum / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D000978:Antiparkinson Agents; D015102:3,4-Dihydroxyphenylacetic Acid; D007980:Levodopa; D008734:Methoxyhydroxyphenylglycol; D001545:Benserazide; D002230:Carbidopa; D004298:Dopamine; D006719:Homovanillic Acid