Disposition of 1,2,3,4,-tetrahydroisoquinoline in the brain of male Wistar and Dark Agouti rats.
Direct evidence for accumulation of 1,2,3,4-tetrahydroisoquinoline (TIQ), an endo- and exogenous substance suspected of producing Parkinsonism in humans, has not yet been shown. This study aimed to examine TIQ disposition in the whole rat brain and in the striatum and substantia nigra (SN). TIQ was administered to male Wistar and Dark Agouti rats (20, 40 and 100 mg/kg i.p.) alone or jointly with specific CYP2D inhibitor quinine (20, 40, 80 mg/kg i.p.), acutely or chronically. TIQ concentration in brain of both strains was several-fold higher than in plasma. The level of its metabolite, 4-OH-TIQ, was very low in the brain and plasma of TIQ-treated Wistar while in those receiving additionally quinine or in Dark Agouti rats, 4-OH-TIQ was absent or negligible. Inhibition of CYP2D catalyzing TIQ 4-hydroxylation in the liver had no influence on TIQ accumulation in the brain. Exogenous TIQ was actively transported from periphery into the brain by the organic cation transporter system, mainly OCT3, and quickly eliminated from it by P-glycoprotein. TIQ accumulation after chronic injection to Wistar rats was short-lasting and limited to SN. High concentration of TIQ in SN induces while in the liver inhibits the nigral and hepatic activity CYP2D, respectively.
Lorenc-Koci
Elzbieta
E
Department of Neuropsychopharmacology, Institute of Pharmacology, Polish Academy of Science, 12 Smetna St., PL-31-343 Kraków, Poland. lorenc@if-pan.krakow.pl
Wójcikowski
Jacek
J
Kot
Marta
M
Haduch
Anna
A
Boksa
Jan
J
Daniel
Władysława Anna
WA
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism*; D019389:Cytochrome P-450 CYP2D6 / Q000172:deficiency* / Q000187:drug effects; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D027701:Organic Cation Transport Proteins / Q000378:metabolism; D011803:Quinine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D044005:Tetrahydroisoquinolines / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism*; D013997:Time Factors
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D004791:Enzyme Inhibitors; D027701:Organic Cation Transport Proteins; D044005:Tetrahydroisoquinolines; C014843:1,2,3,4-tetrahydroisoquinoline; D011803:Quinine; D019389:Cytochrome P-450 CYP2D6