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Metabolite kinetics after oral drug administration can be determined, without separate metabolite administration, using the concepts of mean residence time (MRT). The MRT of parent drug and metabolite after oral administration of the parent drug, MRTp,p(oral) and MRTm,p(oral), can be calculated directly from the drug and metabolite profiles. The difference between MRTm,p(oral) and MRTp,p(oral), termed Delta MRT, yields an estimate of MRT of metabolite when the metabolite is given as an iv bolus, MRTm,m(iv). The calculation is simple for drugs that are known to undergo negligible first-pass metabolism. Correction can also be made when extent of first-pass metabolism is known. Ambiguity is encountered, however, when the degree of first-pass metabolism is unknown. When the delta MRT is negative, then first-pass metabolism must be considered. A positive value of delta MRT, on the other hand, is not a definitive indication of the absence of first-pass metabolism. It may occur in the presence or absence of first-pass metabolism. Ignoring the possibility of first-pass metabolism when a positive value of delta MRT occurs may lead to an incorrect estimate of MRTm, m(iv). The estimation error is relatively small, however, when MRTm,m(iv) MRTp,p(iv), even when first-pass metabolism is extensive. This situation may apply to the administration of a prodrug. 相似文献
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M Gibaldi 《The Annals of pharmacotherapy》1992,26(12):1589-1594
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J. E. Axelson M. Gibaldi W. D. Conway 《Xenobiotica; the fate of foreign compounds in biological systems》2013,43(10):585-593
The gastro-intestinal absorption and metabolic fate, after intravenous and intraperitoneal administration, of [3H]N, N-bis(phenylcarbamoylmethyl)dimethylammonium chloride (QX-572), a lidocaine derivative with anti-arrhythmic activity, has been investigated in the rat.Only about one-third of the dose is absorbed after oral administration to fasted animals. Pre-feeding of rats markedly diminishes the apparent availability of the drug. Co-administration of salicylate results in about 50% increase in the absorption of QX-572.After intravenous administration of [3H]QX-572 to normal rats, urinary excretion of 3H is 60% greater than after intraperitoneal administration. Total urinary recovery of 3H is similar after intravenous or intraperitoneal administration to rats with ligated bile ducts, although much higher than that observed in non-ligated rats.Urinary excretion data suggest that in normal rats apparent QX-572 is excreted in bile to a much greater extent after intraperitoneal than after intravenous administration. The total cumulative 3H recovered from rat bile 24 h after administration of [3H]QX-572 was about 65% greater after intraperitoneal than after intravenous administration.One metabolite, possibly a carboxylic acid, was excreted in the urine along with unchanged drug. Irrespective of the route of administration about 70% of the total 3H in the urine represented unchanged drug and the metabolite accounted for the balance. Essentially, no intact drug was found in the bile. The same metabolite as identified in the urine accounted for about 80% of total 3H in the bile.In the rat QX-572 undergoes significant first-pass metabolism and the metabolite is rapidly cleared from liver to bile. 相似文献
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