Harry B. Kostenbauder

Bioavailability and single‐dose pharmacokinetics of intramuscular phenytoin

Comparison of phenytoin plasma concentrations in an intravenous and intramuscular crossover study in 12 healthy ambulant, male subjects indicates that phenytoin administered intramuscularly is absorbed over a period of approximately five days. A model simulating precipitation and redissolution of the drug at the injection site has been shown to satisfactorily fit observed plasma concentration data following intramuscular administration. It is proposed that this model will be useful in the selection of an appropriate dosing regimen in situations in which intramuscular administration of phenytoin is indicated.

Reinforcing and other behavioral effects of nicotine

Published findings of intravenous nicotine self-injection indicate that the reinforcing properties of nicotine are weak when the drug is made available according to continuous reinforcement (CRF) or fixed-ratio (FR) schedules. CRF self-injection rates are generally only 2-3 times saline control levels and self-injection frequency is largely insensitive to changes in unit dose. In contrast, drugs of the psychomotor stimulant, opiate, and sedative-hypnotic classes, with similar pharmacokinetic parameters, maintain much higher self-injection rates and show systematic changes in rate with unit dose variations. Recent studies using interval and second-order schedules of nicotine presentation have been more successful in maintaining higher rates of self-administration behavior. Systematic dose-response functions have also been found under these conditions. Food-deprivation, species and strain differences, circadian rhythms, and duration of exposure to the drug also appear to be important variables in determining self-injection rate. Finally, the rapid development of tolerance to the effects of nicotine may account for changes in the pattern of self-administration within daily sessions and the differential sensitivity of those patterns to nicotine pretreatment.

Maintenance of therapeutic phenytoin plasma levels via intramuscular administration.

A parenteral dosing regimen was designed for the immediate attainment and maintenance of therapeutic plasma levels of phenytoin in patients requiring anticonvulsant therapy, but not able to tolerate oral medication. An intravenous dose of 10.7 mg/kg body weight infused at a rate of 25 mg/min immediately followed by an intramuscular dose of 12.7 mg/kg body weight were administered initially. This was followed by daily intramuscular maintenance doses, generally 8.6 mg/kg body weight, until oral medication could be tolerated. Due to variability between subjects, primarily in metabolism, the predicted maintenance doses had to be adjusted in approximately one third of the patients. This regimen for the dosing of phenytoin was evaluated in 98 patients and consistently yielded therapeutic levels.

Increase of hexobarbital sleeping time and inhibition of drug metabolism by the major metabolite of diphenylhydantoin

Abstract The major metabolite of diphenylhydantoin, 5-(p-hydroxyphenyl)-5-phenylhydantoin, has been shown to inhibit hexobarbital and ethylmorphine metabolism by a rat liver homogenate, and to markedly prolong hexobarbital sleeping time in mice. Such cross-inhibition of metabolism among drugs which are detoxified by formation of hydroxylated metabolites represents an example of a drug-drug interaction which must be taken into account when describing the behavior of drugs in the body.

The effect of ion-pair formation on the lethal dose of methantheline bromide.

Abstract Addition of neutralized trichloracetic acid to solutions containing methantheline bromide increased the lethal dose of methentheline bromide. This might be attributed to an increase in distribution of the drug in the body due to increased lipophilicity of the ion-pairs. Formulations of drugs as ion-pairs to increase distribution and decrease toxicity is a possibility.

Quantification of propranolol enantiomers in small blood samples from rats by reversed-phase high-performance liquid chromatography after chiral derivatization

A high-performance liquid chromatographic (HPLC) technique is described for quantification of R(+)- and S(-)-propranolol from 100-microliters rat blood samples. The procedure involves chiral derivatization with tert.-butoxycarbonyl-L-leucine anhydride to form diastereomeric propranolol-L-leucine derivatives which are separated on a reversed-phase HPLC column. The method as previously reported has been modified for assaying serial blood microsamples obtained from the rat for pharmacokinetic studies. An internal standard, cyclopentyldesisopropylpropranolol, has been incorporated into the assay and several derivatization parameters have been altered. Standard curves for both enantiomers were linear over a 60-fold concentration range in 100-microliters samples of whole rat blood (12.5-750 ng/ml; r = 0.9992 for each enantiomer). Inter- and intra-assay variability was less than 12% for each enantiomer at 25 ng/ml. No enantiomeric interference or racemization was observed as a result of the derivatization. No analytical interference was noted from endogenous components in rat blood samples. Preliminary data from two male Sprague-Dawley rats given a 2.0 mg/kg intravenous dose of racemic propranolol revealed differential disposition of the two enantiomers. R(+)-Propranolol achieved higher initial concentration but was eliminated more rapidly than S(-)-propranolol. Terminal half-lives of R(+)- and S(-)-propranolol were 19.23 and 51.95 min, respectively, in one rat, and 14.50 and 52.07 min, respectively, in the other.

The Effect of Some Cigarette Smoke Constituents and other Compounds on the Metabolism of Benzo(a)pyrene in Rabbit Lung 9000 g Supernatant

1. The inhibitory effects, of a number of compounds, on the formation of two groups of benzo(a)pyrene metabolites in rabbit lung homogenates (9000 g supernatant) have been investigated. 2. The inhibitors comprised two groups: those inhibiting primarily benzo(a)pyrene hydroxylase activity, and those inhibiting the activity of the epoxide-metabolizing enzymes as well as hydroxylase activity. Phenol, 1-naphthol, nicotine and acetone belong to the former group; naphthalene, anthracene and chlorpromazine to the latter group. 3. The most active inhibitors also caused a significant decrease in the amount of benzo(a)pyrene bound covalently to tissue macromolecules.

Phenoxybenzamine stability in aqueous ethanolic solutions. I. Application of potentiometric pH stat analysis to determine kinetics

Abstract The kinetics of decomposition of phenoxybenzamine (I) were determined as a function of apparent pH in 1:1 absolute ethanol : water. Decomposition proceeds through reversible cyclization to an unprotonated ethylenimonium ion [N-benzyl-N-(1-phenoxy-2-propyl)ethylenimoniumion, II], which then reacts with both water and ethanol to form solvolysis products. Both I and solvolysis products are weak bases that exist partially protonated. Decomposition of I involves the formation of titratable hydrogen ion from protonated I as II is formed. Solvolysis of II yields titratable hydrogen ion as the products are formed. At apparent pH values of 4.50 and below, all titratable hydrogen ion may be assigned to the cyclization process. At apparent pH values of 6.50 and above all titratable hydrogen ion may be assigned to the solvolysis process. This unambiguous assignment of titratable hydrogen ion to the individual processes allows individual rate constants to be determined from pH stat data only. Complementary analytical methods such as chloride ion analyses are unnecessary to elucidate the kinetics of I decomposition. The rate of cyclization was pH-dependent due to reaction of unprotonated I only. The pK a of the conjugate acid of I was 5.01 and the specific rate constant for cyclization was 0.293 min −1 . The reversibility of the cyclization reaction was found to be minimal. The rate constant for the reaction between II and chloride ions to form I was 4 × 10 −6 M · min −1 . The solvolysis was found to be pH-independent with a rate constant of 0.0289 min −1 .

Isolation of a cigarette smoke fraction responsible for the inhibition of benzo[a]pyrene metabolism in the isolated perfused rabbit lung

Among the several thousand components of cigarette smoke is a substance or substances capable of inhibiting pulmonary metabolism of nicotine and altering the metabolite profile of procarcinogens such as benzo[a]pyrene (BP). This substance(s) inhibits BP metabolism in the lung in amounts present in a few puffs of cigarette smoke. By a series of extractions and chromatographic methods an active subfraction containing only 1% of the total cigarette smoke condensate (CSC), was isolated. This fraction demonstrated the same inhibition of BP metabolism in the isolate perfused lung (IPL) as the whole smoke. The inhibitor(s) present in this fraction possess amphoteric characteristics. The acidic function is believed to be a phenolic one.

Phenoxybenzamine stability in aqueous ethanolic solutions. II. Solvent effects upon kinetics

Abstract Determination of phenoxybenzamine (I) cyclization kinetics utilizing the pH stat method required that studies be conducted at apparent pH values below the apparent pK a values of the drug. This condition confers the benefit of improved I solubility and enables the cyclization rate constant (k 1,app ) to be measured in solvent mixtures from 7: 3 ethanol:water up to and including water. I conjugate acid apparent pK a values were determined in solvents up to 4:6 ethanol:water and allowed specific rate constants for cyclization (k 1 ) to be determined over the 7:3 to 4:6 ethanol:water range. A semilogarithmic plot of k 1 versus solvent ionizing power was linear and enabled values over the 3:7 to 0:10 ethanol:water range to be obtained by extrapolation. The apparent pK a of I conjugate acid in water was calculated from experimental k 1,app and extrapolated k 1 values in water. The ethylenimonium ion [N-benzyl-N-(1-phenoxy-2-propyl)ethylenimonium ion, II] solvolysis rate constants (k 2 , the sum of the individual rate constants k w and k alc for reaction of II with water and ethanol, respectively) were obtained over the 1:1 to 3:7 ethanol:water range. The pH stat method required that this process be measured at apparent pH values above the apparent pK a , where drug solubility is low. k 2 in water was thus estimated by extrapolation of a log k 2 versus dielectric constant reciprocal plot. The rate constant for reformation of I (k −1 ) was negligible over the 3:7 to 0:10 ethanol:water range.