Pharmacokinetics and pharmacodynamics of quinidine and its metabolite, quinidine-N-oxide, in beagle dogs.

Quinidine and one of its major metabolites, quinidine-N-oxide, were given by separate i.v. infusions to each of three beagle dogs.

Induction of quinidine metabolism and plasma protein binding by phenobarbital in dogs.

Two porta-caval transposed mongrel dogs were studied for phenobarbital (PB) induction of quinidine disposition after separate quinidine infusions via normal intravenous route and via portal vein. The plasma concentrations of quinidine and of three metabolites measured (3-OH quinidine, quinidine N-oxide, quinidine 10,11-dihydrodiol) were quite similar between i.v.

Nonlinear formation of propranolol metabolites in dogs after portacaval transpositions.

The formation of four major metabolites of propranolol by the liver was examined at steady state in three dogs that had undergone surgical portacaval transposition, following which injection of drug into the hindlimb delivers the total dose to the liver. Propranolol was infused directly into the liver via a hindlimb vein at dose rates ranging from 1.01 to 6.

Determination of picogram nitroglycerin plasma concentrations using capillary gas chromatography with on-column injection.

A specific, sensitive, and precise capillary gas chromatographic (GC) assay capable of analyzing picogram concentrations of nitroglycerin in human plasma was developed. The analytical procedure involves a double extraction of 1 mL of plasma with pentane, after the addition of internal standard (1 ng of 2,6-dinitrotoluene), followed by evaporation and reconstitution in 50 microL of heptane. The extract (1 microL) was injected onto a capillary column using the on-column injection technique.

Pharmacokinetics of quinidine and three of its metabolites in man.

Disposition parameters of quinidine and three of its metabolism, 3-hydroxy quinidine, quinidine N-oxide, and quinidine 10,11-dihydrodiol, were determined in five normal healthy volunteers after prolonged intravenous infusion and multiple oral doses. The plasma concentrations of individual metabolites after 7 hr of constant quinidine infusion at a plasma quinidine level of 2.9 +/- (SD) 0.

Estimation of absolute bioavailability assuming steady state apparent volume of distribution remains constant.

The limitations of using estimates of extent of bioavailability (F) based on the assumption that either clearance (CL) or Varea remain, constant are discussed in relation to the situation where CL changes between doses. When estimates of F assume CL to remain constant, the extent of the error is the same for all drugs where the percentage change in CL is the same. Assuming Varea to remain constant, the error in F will vary between drugs for similar percentage changes in CL and is related to the extent to which the kinetics of the disposition process deviate from a one compartment body model.

Dependence of renal clearance on urine flow: a mathematical model and its application.

A mathematical model is developed to explain the dependence of renal clearance on urine flow rate. The model is tested using human data from the literature on compounds that are neither secreted nor reabsorbed by active or pH-sensitive mechanisms. The physiologically derived model explains and predicts the relationship between renal clearance and urine flow for a broad spectrum of compounds (i.

Disposition of caffeine and its metabolites in man.

The disposition of caffeine and its metabolites was studied in six healthy subjects by use of sensitive and specific assays. The primary degradation of caffeine in man was found to be N-demethylation and/or ring oxidation to theophylline, paraxanthine, theobromine and 1,3,7-trimethyluric acid. These compounds were further degraded to dimethylated uric acids, monomethylxanthines and monomethyluric acids.

Urine flow-dependence of theophylline renal clearance in man.

Theophylline renal clearance is highly dependent on urine flow rate and is neither concentration nor dose related. To examine the flow dependency, theophylline was administered in single doses (4.3 mg/kg to 8.

Improved liquid-chromatographic assay of quinidine and its metabolites in biological fluids.

We describe a simple, rapid, and specific assay for quinidine and its known metabolites in plasma, urine, and bile. Plasma proteins are precipitated by adding acetonitrile, which also contains the internal standard. The supernatant fluid is evaporated and the reconstituted residue is separated on a reversed-phase column, with fluorescence detection.

Stereoselective disposition and glucuronidation of propranolol in humans.

Following oral dosing to steady state, the disposition of S(-)- and R(+)-propranolol and their corresponding glucuronide conjugates was studied in 4 healthy adults using doses from 40 to 320 mg/day of the racemate. Steady -state plasma concentrations of S(-)-propranolol and its corresponding glucuronide conjugate were greater than that for R(+)-propranolol and its corresponding conjugate. The average steady-state concentration of both enantiomers increased disproportionately to dose.

Lack of gastrointestinal metabolism of propranolol in dogs after portacaval transposition.

We studied whether or not propranolol underwent presystemic metabolism in the gastrointestinal wall in five dogs. The dogs were studied before and four weeks after creation of a portacaval transposition. Before surgery, systemic bioavailability of the oral dose was 8 +/- 8% (mean +/- S.

A technique to study hepatic and intestinal drug metabolism separately in the dog.

A model to study hepatic and intestinal drug metabolism in the dog has been evaluated. The model is made by performing a portacaval transposition, cholecystectomy and inserting a Thomas cannula into the duodenum. The result is a healthy animal in which drugs can be infused either in a normal i.

A method for estimating within-individual variability in clearance and in volume of distribution from standard bioavailability studies.

Bioavailability studies are commonly undertaken, and most, because they involve subjects taking repeated doses of a drug, contain information on intraindividual variability in pharmacokinetics. However, because in such studies bioavailability itself is unknown, it is difficult to resolve which pharmacokinetic parameters vary within individuals. A mathematical model is presented which permits estimation of variability in clearance and in volume of distribution.

An automated HPLC assay for simultaneous quantitation of methylated xanthines and uric acids in urine.

To investigate the elimination kinetics of caffeine and its metabolites, as well as the interaction between them, an automated HPLC method is described. This method involves a single extraction procedure, followed by a gradient elution. Fourteen methylated xanthines and uric acids are well separated with an assay sensitivity of 1 microgram/ml when one-half ml of urine is used.

An automated HPLC method for the assay of propranolol and its basic metabolites in plasma and urine.

An automated HPLC method is described for the simultaneous determination of propranolol, 4-hydroxypropranolol, and N-desisopropylpropranolol in plasma and urine before and after beta-glucuronidase/aryl sulfatase treatment. It involves extraction with ether at pH 10 in the presence of ascorbic acid, added to prevent oxidation of 4-hydroxypropranolol. The compounds are then back extracted into dilute acid and assayed on an HPLC using a fluorescence detector.

Nonlinear theophylline elimination.

Elimination kinetics of theophylline and its major metabolites were investigated in 14 healthy adults in single-dose studies and in a multiple-plateau study. The plasma concentrations of theophylline and the metabolites 3-methylxanthine (3-MX), 1-methyluric acid (1 MU), and 1,3-dimethyluric acid (13-MU) were monitored to about 0.020 mg/l and became convex descending at concentrations below 1 mg/l after single theophylline doses.

Altered quinidine disposition in a patient with chronic active hepatitis.

A 49-year-old female with chronic active hepatitis and ventricular ectopic activity was given i.v. 600 mg quindine gluconate (4·4 mg/kg).

Isolation, characterisation and synthesis of a new quinidine metabolite.

In addition to the well-known quinidine metabolites, 2'-quinidinone and 3-hydroxy-quinidine, a third metabolic product was detected in the plasma of cardiac patients receiving quinidine therapy. Mass spectroscopic, 13C- and 1H-NMR studies, together with information on UV and IR properties of the isolated and also synthetically accessible compound, suggested the presence of an aliphatic N-oxide group. The structure of quinidine-N-oxide for the hitherto unknown metabolite was finally confirmed by X-ray diffraction analysis.

Metabolism of theophylline to caffeine in adults.

Caffeine and its major metabolite, paraxanthine, were observed in plasma following oral administration of theophylline in a multiple dose study. At steady state, plasma caffeine concentrations varied from 0.21 to 0.

Effect of erythromycin on theophylline kinetics.

The effect of erythromycin base on theophylline kinetics was studied in eight informed, nonsmoking, adult males who received a 15-min infusion of theophylline (aminophylline) 5 mg/kg, prior to (control) and after (experimental) a 7-day course of 1 gm daily erythromycin base (E-Mycin). Each subject acted as his own control. Multiple serum samples were collected for 24 hr after each dose and were analyzed for theophylline by high-pressure liquid chromatography.