Kinetics of Drug Absorption, Distribution, Metabolism, and Excretion

Nelson, Eino

doi:10.1002/jps.2600500302

Cited by 122 publications

(38 citation statements)

References 39 publications

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“…The volume of distribution of warfarin (approximately 13%o of body weight) was lower than that of most acidic drugs (25 to 30%) (17) and was identical with that found for pure albumin (21). We previously showed that 97%o of warfarin in plasma is bound to protein (16).…”

Section: Discussionsupporting

confidence: 67%

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Studies on the Coumarin Anticoagulant Drugs: The Pharmacodynamics of Warfarin in Man*

O’Reilly¹,

Aggeler²,

Leong³

1963

J. Clin. Invest.

200

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Link (1) suggested in 1948 that the coumarin compound warfarin be used as a rodenticide. Its first human use was in a suicide attempt in 1952 (2). Although warfarin has been employed increasingly in the treatment of thromboembolic disorders (3)(4)(5), no published reports of its physiologic disposition in man have appeared, probably owing largely to the lack of a suitable method for its measurement in biologic fluids (6).Weiner, Brodie, and Burns (7,8) stated that the half-life of warfarin in man is 90 hours, but did not include the assay method, or give supporting data. In 1953, Yuyama, Goto, and Umezu (9) described a colorimetric method for the estimation of warfarin in rat plasma, but apparently this method was never applied to man. Since 1954, several investigations of warfarin in the rat have appeared, including the studies of Garner (10), Eble (11), and Lin (12). Their methods, however, were unpublished except as doctoral theses, or were not readily adaptable for studies in man.Recently, we described a spectrophotometric method for the estimation of warfarin in biologic fluids (13), and have used this method in the present study to investigate the pharmiacodynamics of warfarin in man. We determined the concentrations of warfarin in the plasma and of a warfarin metabolite in the urine of normal subjects after both oral and intravenous administration of the drug. Analysis of the data provided information on its absorption, elimination, apparent volume of distribution, and excretion. Differences in its biologic effect were evaluated by simultaneous measurements of its plasma concentration and of prothrombin complex activity. * Work supported by U. S. Public Health Service grant H-2754. METHODSThe subjects, all volunteers, were 14 normal men and women, ages 27 to 63 years, and one patient, age 72 years, with coronary artery disease who was included because he was unusually resistant to the prothrombinopenic effects of the drug.Warfarin sodium 1 was administered either orally in the form of tablets (starch base) or by iv injection. The tablets were swallowed whole in the morning by subjects in the postabsorptive state, and no food was taken for at least 2 hours thereafter. For iv administration, lyophilized warfarin sodium was reconstituted in distilled water. The total dose was injected into the antecubital vein in less than 1 minute. The dose of warfarin given by either route was based on body weight in an attempt to equalize the effect of the drug on subjects with different plasma volumes, assumed to be a function of body weight. A standard dose of 1.5 mg per kg of body weight was selected so that drug levels and prothrombin complex responses would be in a clearly measurable range for several days after administration of warfarin.Test specimens were prepared as follows. Blood obtaimed by clean venipuncture was mixed in glass tubes in a proportion of 9: 1 with 3.2% sodium citrate in 0.7%c saline and centrifuged at 2,000 rpm for 20 minutes at 4°C.

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Section: Discussionsupporting

confidence: 67%

“…Since practically no unchanged warfarin was excreted in the urine and none in the stool (13), its elimination from the plasma must occur almost exclusively by chemical transformation (17). The speed of its elimination is a function of the rate of this process.…”

Section: Discussionmentioning

confidence: 99%

Studies on the Coumarin Anticoagulant Drugs: The Pharmacodynamics of Warfarin in Man*

O’Reilly¹,

Aggeler²,

Leong³

1963

J. Clin. Invest.

200

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“…A noninvasive method based on F urinary excretion data was used to study pharmacokinetic variables of the drug [16]. F was administered intravenously (12 patients) or intramuscularly (2 patients) as a single injection at a dose of 1 mg/kg body weight.…”

Section: Study Proceduresmentioning

confidence: 99%

Kinetics of Urinary Furosemide Elimination in Infants

Prandota¹,

Houin²

1984

Dev Pharmacol Ther

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Using a one-compartment model, the urinary elimination kinetics of a single intravenous 1 mg/kg dose of furosemide (F) was studied in 13 infants, 9 days to 12 months old (mean 3.7 ± (SD) 3.48 months old), and 1, 23-month-old child, with bilateral multifocal pneumonia, recovering from respiratory and cardiac insufficiency accompanying pneumonia and/or other diseases. F elimination half-life was determined with the use of a noninvasive method based on the drug’s urinary excretion data. The drug urinary elimination t(½) in the infants ranged from 0.654 to 3.29 h. Cumulative excretion of F in the infants' urine was similar to the values in healthy adults. Since the furosemide urinary half-lives found in infants were similar to the data reported in older children and healthy adults it is suggested that immaturity of renal function during the 1st year of life, i.e. in older infants, has no evident effect on the elimination kinetics of a 1 mg/kg intravenous dose of F. Mean F urinary elimination t(½) in infants with pneumonia and cardiac insufficiency was significantly longer compared with the F(t½) found in children with the pneumonia alone (2.15 vs. 1.01 h, respectively), suggesting slower elimination of the drug in these patients.

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“…During the 1950s and 1960s, the discipline of pharmacokinetics was landmarked by major contributions from Goldstein (6), Dost (5), Nelson ( 10) …”

Section: Pharmacokineticsmentioning

confidence: 99%