Cell membrane transport of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the liver and systemic bioavailability.
Modulation of hepatic disposition of MPTP could influence susceptibility to its neurotoxicity. Therefore, we studied hepatocellular transport of MPTP in the perfused rat liver and isolated rat hepatocytes. The perfused liver extensively extracted MPTP. Amiloride and tubocurarine, inhibitors of OCT1, increased MPTP recovery (253 +/- 78 and 283 +/- 64%, respectively) and reduced PS(influx) (0.69 +/- 0.36 to 0.27 +/- 0.11, and 0.97 +/- 0.50 to 0.23 +/- 0.05 ml/s/g, respectively). P-glycoprotein inhibitor, daunomycin, and Oatp 1 & 2 inhibitor, rifamycin, had no effect. In isolated hepatocytes, amiloride and tubocurarine increased hepatic uptake of MPTP (23 +/- 12 and 6 +/- 2%, respectively). Daunomycin reduced MPTP uptake by 22 +/- 8% and rifamycin had no effect. Only a small proportion of MPTP is taken up into hepatocytes by transporters; however, modulation of these transport mechanisms will influence systemic bioavailability.
Yang
M C
MC
Canberra Clinical School of the University of Sydney, Canberra Hospital, Garran, ACT, Australia 2065. Maria.Yang@anu.edu.au
McLean
A J
AJ
Le Couteur
D G
DG
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000493:pharmacokinetics*; D000584:Amiloride / Q000494:pharmacology; D000818:Animals; D001682:Biological Availability; D001693:Biological Transport, Active / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D003630:Daunorubicin / Q000494:pharmacology; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D020267:MPTP Poisoning / Q000209:etiology / Q000378:metabolism; D008297:Male; D009498:Neurotoxins / Q000493:pharmacokinetics / Q000633:toxicity; D027702:Organic Cation Transporter 1 / Q000378:metabolism; D010477:Perfusion; D051381:Rats; D017208:Rats, Wistar; D012294:Rifamycins / Q000494:pharmacology; D014403:Tubocurarine / Q000494:pharmacology
D009498:Neurotoxins; D027702:Organic Cation Transporter 1; D012294:Rifamycins; D000584:Amiloride; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D014403:Tubocurarine; D003630:Daunorubicin