In vivo pharmacokinetics of aldose reductase inhibitors: 3-fluoro-3-deoxy-D-glucose NMR studies in rat brains.
Direct quantification of the inhibitory effects of orally administered drugs (sorbinil, cyclandelate and sulindac) on aldose reductase activities in rat brains was performed non-invasively using the 3-fluoro-3-deoxy-D-glucose (3-FDG) 19F NMR spectroscopic technique. Quantitative data obtained directly from the target organ (brain) allowed for unprecedentedly accurate analysis of drug effects in the brain in vivo. Sorbinil, a potent aldose reductase inhibitor, exhibited a classic monophasic organ response, whereas cyclandelate and sulindac showed biphasic suppression patterns. The latter indicate that there are metabolites of these drugs which possess aldose reductase inhibitory activities. The estimated potency of aldose reductase inhibition for each of the three drugs in this study was significantly discrepant from the in vitro studies indicating the complicated nature of the bioavailability of a pharmaceutical agent in vivo, especially where pharmacologically active metabolites of a given drug are involved. Our method allows for a direct quantitative assay and hence the most reliable technique for evaluating aldose reductase inhibitory activities in the target organ.
Kwee
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Neurochemistry Research Laboratory, Veterans Administration Medical Center, Martinez, California 94553.
Nakada
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D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D001921:Brain / Q000201:enzymology*; D003495:Cyclandelate / Q000493:pharmacokinetics*; D007093:Imidazoles / Q000493:pharmacokinetics*; D048289:Imidazolidines; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008333:Mandelic Acids / Q000493:pharmacokinetics*; D051381:Rats; D011919:Rats, Inbred Strains; D013401:Sugar Alcohol Dehydrogenases / Q000037:antagonists & inhibitors*; D013467:Sulindac / Q000493:pharmacokinetics*
D007093:Imidazoles; D048289:Imidazolidines; D008333:Mandelic Acids; D013467:Sulindac; D003495:Cyclandelate; D013401:Sugar Alcohol Dehydrogenases; D000449:Aldehyde Reductase; C026411:sorbinil