Gerald J. Yakatan

Pharmacokinetics of dextromethorphan after single or multiple dosing in combination with quinidine in extensive and poor metabolizers.

Dextromethorphan (DM) pharmacological properties predict that the widely used cough suppressant could be used to treat several neuronal disorders, but it is rapidly metabolized after oral dosing. To find out whether quinidine (Q), a CYP2D6 inhibitor, could elevate and prolong DM plasma profiles, 2 multiple‐dose studies identified the lowest oral dose of Q that could be used in a fixed combination with 3 doses of DM. A multiple‐dose study in healthy subjects with an extensive or a poor enzyme metabolizer phenotype evaluated the safety and pharmacokinetic profile of a selected fixed‐dose combination (AVP‐923). Study 1 randomized 46 healthy subjects, who were extensive CYP2D6 metabolizers, to receive 0, 2.5, 10, 25, 50, or 75 mg Q twice daily in combination with 30 mg DM for 7 days. Plasma and urine samples were collected after the first and last doses for the assay of DM, dextrorphan (DX), and Q. Study 2 randomized 65 healthy extensive CYP2D6 metabolizers to 8 groups given twice‐daily 45‐ or 60‐mg DM doses combined with 0, 30, 45, or 60 mg Q for 7 days. The effects of increasing Q were not different with doses greater than 25 mg, whereas lower doses showed a dose‐related increase in plasma DM concentrations. Urinary ratios of DM/DX showed a Q dose‐ and time‐related increase in the number of subjects converted to the poor metabolizer phenotype that reached 100% on day 3 of dosing with 25 mg Q. Results from both studies indicated that 25 to 30 mg Q is adequate to maximally suppress O‐demethylation of DM. Study 3 evaluated 7 extensive metabolizers and 2 poor metabolizers given an oral capsule every 12 hours containing 30 mg Q combined with 30 mg DM. DM plasma AUC values increased in both groups of subjects during the 8‐day study. The mean urinary metabolic ratio (DM/DX) increased at least 27‐fold in extensive metabolizers by day 8. There was no effect of Q on urinary metabolic ratios in poor metabolizers. Safety evaluations, including electrocardiograms, indicated that the combination was well tolerated, with no difference between extensive and poor metabolizer phenotypes.

Kinetics and mechanism of hydrolysis of furosemide

Abstract Furosemide, a potent diuretic, has been found to give a low bioavailability profile when administered orally which potentially could be due to hydrolysis of the drug prior to absorption. An in vitro kinetic study was performed to elucidate the kinetics and hydrolysis mechanism of furosemide as a function of pH and temperature. In the acidic pH region, below the reported pKa of 3.8, the log K-pH profile indicated specific hydrogen ion catalysis on the undissociated species. In the basis pH region, furosemide hydrolysis is extremely slow. Using the Arrhenius parameters obtained from the studies, furosemide would have a half-life of 178 min under physiological conditions in the stomach of pH 1.0 and temperature of 37°C.

The Effect of Probenecid on Nafcillin Disposition

Abstract: Five normal male volunteers participated in an open crossover study designed to examine the disposition of nafcillin given intravenously with and without probenecid. Each subject received two 500 mg iv doses of sodium nafcillin seven days apart, one dose without probenecid and another dose during oral probenecid administration of 1.0 Gm at bedtime prior to the study day and 1.0 Gm two hours before the nafcillin dose. Blood and urine samples were collected for 10 hours after nafcillin dosing. Assay for nafcillin concentrations was performed via the cup‐plate technique with M. Iuteus. Administration of probenecid significantly increased and prolonged circulating plasma concentrations of nafcillin. Probenecid administration significantly, decreased the per cent of nafcillin recovered in the urine (30% vs. 16.9%). Probenecid pretreatment increased the ana under the plasma drug concentration‐time curve (AUC) two‐fold and decreased the total body clearance significantly with decreases in both renal and non‐renal clearance. K12/k21 and Vc did not significantly change with probenecid. Because probenecid coadministration did not appear to change nafcillin distribution while increasing and prolonging plasma concentrations, probenecid can be recommended to be given concurrently when high nafcillin plasma concentrations are desirable. Changes in plasma concentrations are apparently due to alterations in both renal and non‐renal clearances of nafcillin.

Pharmacokinetic considerations in exchange transfusion in neonates

Neonates undergoing blood exchange often receive concomitant therapy. Questions may be raised whether dosage regimen alterations are necessary to replace drug lost as a result of the exchange procedure. Our study reports the changes in plasma concentration of kanamycin during an exchange transfusion and a pharmacokinetic analysis of the effect of the exchange on drug elimination. The relationships of the volumes of distribution, elimination rate constant, and time after dosing on the fraction of the dose eliminated in the blood exchange are developed on the basis of a one‐compartment body model. Computer simulations using the equations developed were used to estimate the fraction of a dose that might be removed as a result of an exchange transfusion. As the disposition rate constant or the apparent volume of distribution increase, i.e., the clearance of the drug increases, the fraction of the dose removed by the exchange process decreases. Thus, significant amounts of drug removal may occur in an exchange transfusion for drugs with low clearance when the exchange is initiated early in the drug dosing interval. In our study, only 3% of the kanamycin dose was removed as a result of the exchange process, and dosing adjustment would not be required. This was in part due to initiation of the exchange late in the dosing interval, although the maximum calculated percentage of the dose which could have been removed under the exchange conditions employed was only 10%.

Enzymatic determination of acetazolamide in human plasma.

Abstract An enzymatic method utilizing carbonic anhydrase has been evaluated for the determination of acetazolamide in human plasma. A modified procedure, which is accurate, precise and rapid and is useful for bioavailability studies, is described.

The Influence of Various Dispersion Methods on the Rate of Dissolution of Sulfabenzamide

AbstractThe solvent and melt methods were employed to prepare solid dispersions with various water soluble carriers and a slightly soluble drug, sulfabenzamide. The carriers investigated included citric acid, succinic acid, dextrose, polyethylene glycol 6000, mannitol and urea. Dispersions with dextrose were superior to other carriers in releasing the drug into solution. Melts with both dextrose and urea produced faster rates of dissolution of sulfabenzamide than the coprecipitates from the solvent method. With mannitol and polyethylene glycol 6000, the coprecipitates produced a faster rate of dissolution of the drug than the melt dispersions.

Influence of Food on the Bioavailability of Trental® (Pentoxifylline) in Man

AbstractPentoxifylline is an investigational drug shown to improve impaired blood flow in diseased microvasculature. The present study objective was to determine the influence of a single test meal on the bioavailability of pentoxifylline. Single 400 mg oral capsule doses of pentoxifylline were administered to 16 healthy adult male volunteers in a complete crossover design in which the subjects received the drug after fasting overnight or 15 minutes following a standard breakfast. The plasma concentrations of pentoxifylline and its major metabolite were determined as a function of time using a gas chromatographic procedure. The AUC values for both parent drug and metabolite for 0 to 10 hours showed no significant difference due to ingestion of food. A significant decrease in peak plasma concentration (p < .05) was shown for parent drug and metabolite when administered with food. The time-to-peak concentration was significantly delayed (p < .001) when the drug was administered with food. Food administered ...

Single-dose fasting bioequivalence assessment of erythromycin stearate tablets in man

The bioequivalence of film-coated erythromycin stearate tablets produced by five different manufacturers was evaluated in a balanced incomplete block design involving the five formulations given to 30 fasted subjects over a 3-week study period. Serum levels of erythromycin activity were determined microbiologically. Statistical analysis of variance was performed on the observed bioavailability parameters: maximum serum concentration Cmax, time to maximum serum concentration (tmax), and area under the serum concentrationtime curve (AUC). There was no statistical difference between formulations for the tmax parameter. Formulation differences were found, however, based on the analysis of variance of the Cmax and AUC parameters. Two products, although not significantly different from one another, showed significantly greater Cmax and AUC values than the other three products.

Decreased Bioavailability of Sustained Release Acetazolamide Dosage Forms

AbstractBioequivalence comparisons of two sustained release and an immediate release acetazolamide dosage form performed in normal human volunteers (n = 18) demonstrated a large statistical difference between the preparations. The sustained release dosage forms were 40-70% less available than the rapid release form based on comparisons of AUC data. Plasma level data from subjects given a suspension of acetazolamide yielded a biological half-life of 8.5 (± 2.54) hours which is twice that reported previously. A comparison of the AUC data and dissolution profiles generated for each dosage form showed a rank order correlation when a pH 1.2 dissolution fluid was used; however, correlation was not evident when the dissolution media was exchanged for pH 4.5 or 7.3 dissolution media.