Peter H. Hinderling

Pharmacokinetics of the antiarrhythmic disopyramide in healthy humans

The pharmacokinetics of the antiarrhythmic disopyramide, 4-diisopropylamino-2-phenyl-2-(2-pyridyl)butyramide phosphate, and its monodealkylated metabolite were investigated in seven volunteers after intravenous (1 and 2 mg/kg) and oral (3 and 6 mg/kg) administration. Unchanged drug (52%) and the monodealkylated metabolite (25%) were renally excreted on intravenous administration. The pharmacokinetics of disopyramide were first order and dose independent only when referenced to the drug not bound to plasma proteins since this binding was dose dependent. The apparent half-lives of the α and β phases on intravenous administration were 2 min and 4.5 hr, respectively. The apparent volumes of distribution of the central and peripheral compartments, referenced to unbound disopyramide in the plasma, were 9 and 80 liters, respectively. The half-life of absorption of oral aqueous disopyramide phosphate was 30 min with a lag time of 16 min and an apparent first-pass metabolism of 16% of the absorbed dose, consistent with the hepatic efficiency of 14%. The renal and metabolic clearances were 125 and 111 ml/min, respectively. Graphical and computer analysis of the plasma and urine data showed dose-independent first-order pharmacokinetics of plasma unbound drug in a two-compartment-body model to give two metabolites and a first-pass transformation of a fraction of the oral dose. The absorption efficiency of unchanged drug was 83%.

Quantitative relationships between structure and pharmacokinetics of beta-adrenoceptor blocking agents in man

The structure and pharmacokinetics relationship of 14-beta-adrenoceptor antagonists was investigated in humans. Statistically significant linear and parabolic correlations were found to exist between standard and derived mean pharmacokinetic parameters and the apparent octanol/buffer (pH7.4) partition coefficient of the compounds. The lipophilic/hydrophilic properties were the primary determinants for the pharmacokinetic behavior of the compounds. Most of the pharmacokinetic parameters were also significantly correlated with the plasma protein/plasma water partition coefficient for the compounds. When the values of the pharmacokinetic parameters of the individual compounds were predicted from the regressions on the apparent partition coefficients in octanol/buffer (pH 7.4) and in plasma protein/plasma water, the error was on average 60%.

The pharmacokinetics of furazlocillin in healthy humans

AbstractThe pharmacokinetics of the novel acylureidopenicillin furazlocillin, 6-[D-2-(3-furfurylidenamino-2-oxo-imidazolidine-1-carboxamido)-2-(4-hydroxyphenyl)-acetamido]-penicillanic acid and of its penicilloic acid derivative were investigated in five healthy male volunteers after intravenous administration of 2 and 4 g dosages. The volunteers were either in a lying or sitting position throughout the duration of the studies. The concentrations of the drug in plasma and urine were measured by two different methods in parallel: a microbiological assay and a newly developed high pressure liquid chromatography method. The latter method was also applicable for quantitation of the penicilloic acid derivative in these biological fluids. The drugs plasma protein binding (66%) and apparent red cell-plasma partition coefficient (0.055) were concentration independent. The pharmacokinetics of the drug were first order only at the lower dose level The apparent half lives of three distinguishable phases were, respectively, 4

Protein Binding and Erythrocyte Partitioning of Disopyramide and Its Monodealkylated Metabolite

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Pharmacokinetics of β-Methyldigoxin in Healthy Humans II: Oral Studies and Bioavailability

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Application of ion‐pair methods to drug extraction from biological fluids II: Quantitative determination of biguanides in biological fluids and comparison of protein binding estimates

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