A comparison of the effects of reversible and irreversible inhibitors of aromatic L-amino acid decarboxylase on the half-life and other pharmacokinetic parameters of oral L-3,4-dihydroxyphenylalanine.
The effects of the irreversible, enzyme-activated, aromatic L-amino acid decarboxylase (AADC) inhibitors alpha-monofluoromethyl-beta-(3,4-dihydroxyphenyl)alanine (MFMD), alpha-difluoromethyl-beta-(3,4-dihydroxyphenyl)alanine (DFMD), and alpha-monofluoromethyl-beta-(2,3-dihydroxyphenyl)alanine (MDL 72. 163) on the serum t1/2 and other pharmacokinetic parameters of co-administered L-3,4-dihydroxyphenylalanine (L-DOPA) were compared to those of the reversible inhibitor, carbidopa in rats. MFMD and MDL 72. 163, administered as their DL-racemic mixtures, produced increases in the t1/2 and bioavailability of co-administered L-DOPA comparable to that produced by a 10-fold larger dose of carbidopa administered as the active L-enantiomer; increasing the dose of MDL 72. 163 did not further increase the t1/2 or bioavailability of L-DOPA. DFMD produced smaller increases of both t1/2 and bioavailability at higher doses. Concomitant decreases in the ClT and aVD were observed with all four inhibitors. Although AADC inhibition reduced the magnitude of the increases in serum dopamine levels following L-DOPA administration, no reduction in serum 3,4-dihydroxyphenylacetic acid levels was observed. The failure of the irreversible inhibitors to produce a larger increase in the t1/2 of L-DOPA than is produced by carbidopa is suggested to reflect the existence of alternative pathways of L-DOPA metabolism.
D000818:Animals; D065105:Aromatic Amino Acid Decarboxylase Inhibitors; D002230:Carbidopa / Q000494:pharmacology; D004295:Dihydroxyphenylalanine / Q000031:analogs & derivatives / Q000494:pharmacology; D006207:Half-Life; D007700:Kinetics; D007980:Levodopa / Q000378:metabolism*; D008297:Male; D008750:Methyldopa / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains
D065105:Aromatic Amino Acid Decarboxylase Inhibitors; D007980:Levodopa; C028477:alpha-difluoromethyl-DOPA; D008750:Methyldopa; D004295:Dihydroxyphenylalanine; C019494:alpha-monofluoromethyldopa; C038465:alpha-monofluoromethyl-beta-(2,3-dihydroxyphenyl)alanine; D002230:Carbidopa