Brain microdialysis and PK/PD correlation of pregabalin in rats

Pregabalin [PGB, (S)-3-isobutyl GABA, CI-1008] is a derivative of the inhibitory neurotransmitter g-aminobutyric acid (GABA). It has shown anticonvulsant, analgesia and anxiety activity in animal models. In this report, blood-brain barrier (BBB) influx and efflux of PGB were investigated with microd...

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Bibliographic Details
Published in:	European journal of drug metabolism and pharmacokinetics Vol. 26; no. 1-2; pp. 123 - 128
Main Authors:	FENG, Meihua Rose, TURLUCK, Daniel, BURLEIGH, Jim, LISTER, Richard, FAN, Conglin, MIDDLEBROOK, Anne, TAYLOR, Charley, SU, Tizi
Format:	Journal Article
Language:	English
Published:	Genève Médecine et hygiène 01-01-2001
Subjects:	Acetates - administration & dosage Acetates - pharmacokinetics Amines Animals Anticonvulsants - administration & dosage Anticonvulsants - pharmacokinetics Anticonvulsants - pharmacology Anticonvulsants. Antiepileptics. Antiparkinson agents Biological and medical sciences Blood-Brain Barrier Brain - metabolism Cyclohexanecarboxylic Acids Electroshock GABA Antagonists - administration & dosage GABA Antagonists - pharmacokinetics GABA Antagonists - pharmacology gamma-Aminobutyric Acid - administration & dosage gamma-Aminobutyric Acid - analogs & derivatives gamma-Aminobutyric Acid - pharmacokinetics gamma-Aminobutyric Acid - pharmacology Indicators and Reagents Infusions, Intravenous Medical sciences Microdialysis Models, Biological Neuropharmacology Pharmacology. Drug treatments Pregabalin Rats Rats, Wistar Seizures - metabolism Pharmacokinetic pharmacodynamic relationship Intravenous administration Rat Rodentia Central nervous system Oral administration Anticonvulsant Permeability Pregabalin Blood brain barrier Vertebrata Mammalia Activity concentration relation Perfusion Animal Distribution Pharmacokinetics Brain (vertebrata)
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Summary:	Pregabalin [PGB, (S)-3-isobutyl GABA, CI-1008] is a derivative of the inhibitory neurotransmitter g-aminobutyric acid (GABA). It has shown anticonvulsant, analgesia and anxiety activity in animal models. In this report, blood-brain barrier (BBB) influx and efflux of PGB were investigated with microdialysis at efficacious doses in rats. BBB influx (CLin) and efflux (CLout) permeability for pregabalin were 4.8 and 37.2 microL/min/g brain, respectively, following an intravenous infusion to rats. The results indicate that PGB is brain penetrable, supporting its anti-epilepsy and other CNS pharmacology. Significant anticonvulsant action of PGB was detected between 2 and 8 hr post oral dose, which is lag behind ECF drug concentrations lees. A PK/PD link model was used to describe the counter-clockwise hysteresis relationship between pregabalin brain ECF concentration and the anticonvulsant effect in rats. The resulting Ce (concentration in effect compartment) versus effect profile exhibits a sigmoidal curve and the calculated ECe50 and Keo values were 95.3 ng/mL and 0.0092 min-1, respectively. The small Keo value suggests that the effect is not directly proportional to the amount of pregabalin in the ECF compartment possibly due to inherent delay.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0378-7966 2107-0180
DOI:	10.1007/bf03190385