Peripheral pharmacokinetic handling and metabolism of L-dopa in the rat: the effect of route of administration and carbidopa pretreatment.
The effect of carbidopa (L-alpha-methyldopa hydrazine; 25 mg kg-1 i.p.) pretreatment on the pharmacokinetics and peripheral metabolism of orally and intra-aortically administered L-3,4-dihydroxyphenylalanine (L-dopa; 50 mg kg-1) has been examined in rats. Following intra-aortic (i.a.) administration, plasma levels of the drug declined biexponentially. Pretreatment with carbidopa resulted in higher plasma concentrations after i.a. administration of L-dopa, but had no effect on the half-life (t1/2) for its distribution or elimination. Oral L-dopa gave peak plasma concentrations at 1.5 h and then a log-linear decline between 1.5 and 6 h. Pretreatment with carbidopa also produced higher plasma concentrations of L-dopa given orally, and the t1/2 for its elimination tended to be increased compared with values achieved after the drug alone. Pretreatment with carbidopa decreased volume of distribution and total plasma clearance and increased area under the curve (0-infinity) after L-dopa i.a. and increased AUC0-infinity after L-dopa p.o. The fraction of the oral dose absorbed through the gut was not affected. Carbidopa pretreatment enhanced the accumulation of 3-O-methyldopa and decreased dopamine levels in plasma after both i.a. and oral administration of L-dopa. Higher plasma concentrations of 3,4-dihydroxyphenylacetic acid and homovanillic acid (HVA) were detected in the plasma after i.a. rather than oral administration of L-dopa and pretreatment with carbidopa greatly reduced these plasma concentrations. However, following oral L-dopa, only HVA levels were reduced by carbidopa pretreatment.(ABSTRACT TRUNCATED AT 250 WORDS)
Parkinson's Disease Society Experimental Research Laboratories, Biomedical Sciences Division, King's College, London, UK.
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Rose
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Jenner
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Marsden
D015102:3,4-Dihydroxyphenylacetic Acid / Q000097:blood; D000284:Administration, Oral; D000818:Animals; D001013:Aorta, Thoracic; D002230:Carbidopa / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D006719:Homovanillic Acid / Q000097:blood; D007275:Injections, Intravenous; D007980:Levodopa / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D014443:Tyrosine / Q000031:analogs & derivatives / Q000097:blood
D015102:3,4-Dihydroxyphenylacetic Acid; D014443:Tyrosine; D007980:Levodopa; D002230:Carbidopa; C008404:3-methoxytyrosine; D006719:Homovanillic Acid