Lewis W. Dittert

Ibuprofen and sulindac kinetics in alcoholic liver disease

Ibuprofen and sulindac kinetics after oral doses were compared in 15 patients with alcoholic liver disease and 29 normal subjects. The patients with alcoholic liver disease were divided into a group with fair hepatic function (FHF) and a group with poor hepatic function (PHF) based on elimination rates of indocyanine green. The effects of alcoholic liver disease on the ibuprofen kinetics were minimal. The absorption of the drug appeared to be delayed in some of the PHF patients, and slight differences were noted in the serum AUC and the elimination rate constant for ibuprofen. The absorption of sulindac was delayed in both PHF and FHF groups of patients, as was the appearance of the active metabolite, sulindac sulfide, and the inactive metabolite, sulindac sulfone. The plasma AUC for sulindac sulfide in patients with poor hepatic function was four times that in normal subjects. The kinetics of sulindac, a pro‐drug that relies on the liver for conversion to an active metabolite, were markedly affected by alcoholic liver disease.

Alprazolam pharmacokinetics in alcoholic liver disease

Abstract: Alprazolam, a triazolobenzodiazepine, was administered to 17 patients with alcoholic liver disease. The pharmacokinetic parameters derived from plasma alprazolam concentrations were compared with data obtained from 17 normal subjects who were matched for age and sex. The rate of absorption of alprazolam was slower in patients with alcoholic liver disease. The time of maximum serum concentration was 3.3 hours, compared with 1.5 hour in normals (P < 0.02). The maximum concentrations, however, did not differ (18.4 vs. 17.2 μg/ml). The elimination half‐life of drug was longer in the patients (19.7 hours) than in the normal subjects (11.4 hours), while the clearance of the drug was slower in the patients with alcoholic liver disease (0.6 vs. 1.2 ml/min/kg). The volumes of distribution (area) did not differ between the two groups (1.1 vs. 1.2 liter/kg). The changes in elimination half‐life and clearance indicate that the metabolism of the drug is slowed in patients with alcoholic liver disease.

Disposition of moracizine (ethmozine) in healthy subjects after oral administration of radiolabelled drug

SummaryMoracizine (ethmozine) is a phenothiazine derivative with demonstrated antiarrhythmic activity. To characterize the pharmacokinetics and material balance relationships in humans, we have given14C-moracizine·HCl as a single oral dose of 500 mg (50 μCi) to six healthy men. Plasma, urine, and faecal samples were collected for 7 days after administration and the concentrations of total radioactivity and intact moracizine were determined by liquid scintillation counting and HPLC, respectively.Urine and faecal recovery accounted for 95% of the administered radioactivity. Most of this radioactivity was found in the faeces (59%). Only 0.05% of the dose was recovered from urine as intact moracizine.The Cmax and AUC for moracizine equivalents of total radioactivity were 4- and 18-fold higher, respectively, than the corresponding values for intact moracizine. Additionally, both the disappearance of total radioactivity from plasma and its excretion rate into urine were slower in comparison to intact drug. Terminal t1/2 values calculated from plasma concentration-time data were 85.2 and 3.5 h for total radioactivity and intact moracizine, respectively. However, based on urinary excretion rates, the t1/2 for total radioactivity was shorter (29.3 h) while the t1/2 for intact drug was comparable (2.7 h) to the results obtained from the plasma data. The oral plasma clearance of moracizine was relatively large (2.2l·min−1), suggesting first-pass metabolism. The estimated oral systemic availability of moracizine was 34%.

Dose‐dependent absorption of disodium etidronate

The gastrointestinal absorption of disodium etidronate (as [14C]disodium etidronate) was investigated in the rat proximal jejunum in‐situ. Studies using various initial concentrations of the drug suggested that etidronate absorption occurred by passive diffusion at initial concentrations below 0.08 M. At initial concentrations above 0.08 M, the rate of absorption was significantly greater than would be expected if passive diffusion was the only mechanism responsible for absorption. Etidronate absorption is not mediated by the carrier mechanism responsible for phosphate ion absorption.

Liquid chromatographic assay for promethazine in plasma using electrochemical detection

Abstract A high pressure liquid chromatographic assay for promethazine in plasma using electrochemical detection is described. The method was found to be quite reliable and efficient when applied to a bioavailability study involing about 1,000 plasma samples. Using 1 ml aliquots, the lowest detectable concentration was found to be 1 ng/ml. The analysis time averaged about 15 min. per sample. Preliminary results show that systemic availability is better following intramuscular administration of promethazine as compared to the rectal and oral routes.

Influence of disodium etidronate on salicylic acid absorption in the rat

*ROBERT P. SHREWSBURY, **TRACEY B. METCALF, t D A N I E L L. WEISS,

Dose-dependent effect of calcium and magnesium etidronate on salicylic acid absorption in the rat.

LEWIS w. DITTERT, *School of Pharmacy, university of North Carolina, Chapel Hill, North Carolina 27514, **Clark County Hospital, Winchester, Kentucky, tDivhion of Medical Sciences, Assembly of Life Sciences, National Research Council, Washington, D. C. and

Influence of Sulfaethidole on the Human Pharmacokinetics of Dicloxacillin

College of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania, U.S. A .

Comparison of the bioavailability of oral, rectal and intramuscular promethazine†

Disodium etidronate affected salicylic acid absorption from the rat small intestine, in‐situ, when instilled into a jejunal segment for different exposure times before the salicylic acid absorption was measured. At low etidronate concentrations and short exposure times, the salicylic acid absorption rate was significantly increased compared with saline controls. At high etidronate concentrations and longer exposure times, the absorption rate was reduced. Etidronate precomplexed with calcium or magnesium ions at low concentrations still enhanced salicylic acid absorption but at high concentrations absorption of salicylic acid was close to saline controls. Intestinal mucosa exposed to high etidronate concentrations showed a progressive structural destruction but with the complexes, there was no visible alteration. It is proposed that a solubilized etidronate complex, formed either in‐situ or administered as such, is responsible for enhancing salicylic acid absorption. This effect is hidden at high etidronate concentrations because of the deterioration of the mucosal surface and at high complex concentrations because these decrease the absorbing surface area and increase the viscosity of the lumen contents.

Competitive Inhibition between Folic Acid and Methotrexate for Transport Carrier in the Rat Small Intestine

In a five-patient crossover study, serum levels of dicloxacillin after intravenous administration of dicloxacillin in the absence and presence of sulfaethiodole were measured. Significantly greater serum concentrations of dicloxacillin were noted when dicloxacillin was administered with sulfaethidole. Pharmacokinetic evaluation of the data suggests that the higher serum concentrations were primarily the result of changes in the extravascular distribution for dicloxacillin in the presence of sulfaethidole. Although examination of the distribution rate constants for dicloxacillin in a two-compartment open model would suggest a lowering of serum concentrations, the experimental data clearly indicate that the serum and tissue compartment dicloxacillin concentrations increased in the presence of sulfaethiodle, indicating that protein binding in the central as well as extravascular compartments could be affected by sulfaethidole.