Randy P. Juhl

Decreased Bioavailability of Digoxin Due to Antacids and Kaolin-Pectin

Employing a Latin-square design and single-dose studies of bioavailability in 10 normal human volunteers, we tested the hypothesis that antacids and kaolin-pectin might interfere with the bioavailability of orally administered digoxin. Cumulative six-day urinary digoxin excretion (expressed as the percentage of a 0.75-mg dose recovered) was: control, 40.1+/-3.0 (S.E.); aluminum hydroxide, 30.7+/-2.9; magnesium hydroxide, 27.1+/-2.4; magnesium trisilicate, 29.1+/-1.7; and kaolin-pectin 23.4+/-2.0. The differences in means were highly significant (F = 10.47, P less than 0.005). Further analysis (multiple comparison test) revealed that control differed significantly from each of the other treatments (alpha = 0.05), but there was no such difference between any of the other treatment groups. The decreased cumulative excretion produced by antacids and kaolin-pectin reflected a striking reduction in digoxin absorption associated with these compounds that was not related to alteration of gut transit time or to adsorption of digoxin to these gastrointestinal medications.

Pharmacokinetics and pharmacodynamics of alprazolam after oral and IV administration.

Six fasting male subjects (20–32 years of age) received an oral tablet and an IV 1.0-mg dose of alprazolam in a crossover-design study. Alprazolam plasma concentration in multiple samples during 36 h after dosing was determined by electron-capture gas-liquid chromatography. Psychomotor performance tests, digit-symbol substitution (DSS), and perceptual speed (PS) were administered at 0, 1.25, 2.25, 5.0, and 12.5 h. Sedation was assessed by the subjects and by an observer using the Stanford Sleepiness Scale and a Nurse Rating Sedation Scale (NRSS), respectively. Mean kinetic parameters after IV and oral alprazolam wre as follows: volume of distribution (Vd) 0.72 and 0.84 l/kg; elimination half-life (t1/2) 11.7 and 11.8 h; clearance (Cl) 0.74 and 0.89 ml/min/kg. There were no significant differences between IV and oral alprazolam in Vd, t1/2, or area under the curve. The mean fraction absorbed after oral administration was 0.92. Performance on PS and DSS tests was impaired at 1.25 and 2.5 h, but had returned to baseline at 5.0 h for both treatments. Onset of sedation was rapid after IV administration and the average time of peak sedation was 0.48 h. Sedation scores were significantly lower during hour 1 after oral administration than after IV, but were not significantly different at later times. Alprazolam is fully available after oral administration and kinetic parameters are not affected by route of administration. With the exception of rapidity of onset, the pharmacodynamic profiles of IV and oral alprazolam are very similar after a 1.0-mg dose.

Effect of oral contraceptives on triazolam, temazepam, alprazolam, and lorazepam kinetics

The effects of low‐dose estrogen oral contraceptives (OC) on the elimination of the oxidized benzodiazepines triazolam (TRZ) and alprazolam (ALP) and the conjugated benzodiazepines temazepam (TMZ) and lorazepam (LOR) were studied in two parallel crossover studies of 20 women each. Women taking OC steroids containing low doses of estrogen and women matched for age, weight, and cigarette smoking received single oral doses of TRZ (0.5 mg) and TMZ (30 mg) or ALP (1 mg) and LOR (2 mg). Kinetics were determined as plasma concentrations during 48 hr after dosing. OCs inhibited the metabolism of ALP: The AUC increased and the elimination rate constant was greater in users of OCs. For TRZ, which has an intermediate extraction ratio, the AUC was increased by OCs but not significantly so. In contrast, OCs decreased the A UC for TMZ and the elimination rate constants for LOR and TMZ. The AUC of LOR was not affected by OCs. Low‐dose estrogen OCs may therefore inhibit the metabolism of some oxidized benzodiazepines and accelerate the metabolism of some conjugated benzodiazepines.

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.

Pharmacodynamic evaluation of the benzodiazepine–oral contraceptive interaction

The sedative, psychomotor, and memory effects of single oral doses of alprazolam (ALP), lorazepam (LOR), temazepam (TMP), and triazolam (TRZ) were evaluated in women taking oral contraceptives (OCs) and a comparable group of control women. Nine women taking OCs and 11 control women took doses of 1 mg ALP and 2 mg LOR and 10 OC users and 10 control women took 30 mg TMP and 0.5 mg TRZ on two occasions separated by 28 days. Minimal psychomotor impairment was noted after TMP. ALP, LOR, and TRZ produced greater performance impairment in the OC users. Correcting the maximum observed performance decrement for plasma concentration did not account for the differences between OC users and controls. After TMP, there was less sedation during the first 2 hours in OC users, who also had higher plasma TMP clearance. There were no differences in sedation between OC users and controls after ALP, LOR, and TRZ; however, there was <50% power to detect a 30% difference. Amnestic effects in OC users and controls did not differ after any of the four drugs. The observed patterns of anterograde amnesia were different, with the earliest and most pronounced recognition failure after TRZ (50% at 1.5 hours), while the LOR effect increased to a maximum (30%) 4 hours after dosing. Our data suggest that differences in benzodiazepine pharmacokinetics between OC users and control women do not account for observed differences in psychomotor impairment. Women taking OCs are more sensitive to the psychomotor effects of single oral doses of benzodiazepines. Statements about sensitivity of OC users to sedative and amnestic effects of benzodiazepines cannot be made with any degree of certainty.

Effect of sulfasalazine on digoxin bioavailability

Low levels of digoxin were noted in a patient receiving digoxin and sulfasalazine (SSA). Discontinuation of SSA resulted in a significant increase in serum digoxin levels. To determine whether or not SSA consistently interfered with the therapeutic effect of digoxin, both drugs were administered to 10 normal subjects in a crossover study. Each received 2 doses of digoxin (0.5 mg, elixir): one dose given alone, and a second dose after 6 days of treatment with SSA. When digoxin was given with SSA, the average area under the serum digoxin curve fell from the control value of 8.79 ng hr ml−1 to 6.66 ng hr ml−1 (p < 0.05), fell and total urinary excretion decreased from 278 mcg/10 days to 228 mcg/10 days (p < 0.025). These changes suggest interference with the bioavailability of digoxin by SSA. Studies were conducted to determine whether SSA inhibited digoxin absorption by physically absorbing the glycoside from solution. In vitro tests failed to reveal any significant adsorptive properties for SSA.

Effects of Aspirin and Ibuprofen on the Pharmacokinetics and Pharmacodynamics of Glyburide in Healthy Subjects

OBJECTIVE: To determine the effects of aspirin and ibuprofen on the pharmacokinetics and pharmacodynamics of glyburide in healthy volunteers. DESIGN: Single-center, randomized, two-way, crossover design following an initial baseline evaluation phase. SETTING: Outpatient, university-based ambulatory care facility. PATIENTS: Sixteen healthy nonsmoking men aged 20–34 years. INTERVENTION: Three phases consisting of six treatments. Phase 1 began with treatment A, a baseline oral glucose tolerance test (GTT), followed by treatment B, glyburide 5 mg plus a GTT. The other two phases were administered in a crossover design. Phase 2 consisted of the administration of aspirin 975 mg qid for 4 days. On day 3 a GTT was administered (treatment C) and on day 4 glyburide 5 mg plus a GTT was administered (treatment E). Phase 3 consisted of the administration of ibuprofen 600 mg qid for 4 days with a GTT on day 3 (treatment D) and glyburide 5 mg plus a GTT on day 4 (treatment F). MAIN OUTCOME MEASURES: Serum glyburide concentrations after each treatment, as well as glucose and insulin, ibuprofen, and salicylate serum concentrations and glyburide free fractions. RESULTS: Aspirin administration resulted in an 85% increase in mean total glyburide oral clearance and a 29% increase in glyburide free fraction. Ibuprofen administration resulted in a slight increase in mean glyburide free fraction, but no significant changes in glyburide pharmacokinetic parameters were observed. Insulin concentrations were increased during the glyburide plus aspirin treatment. Conflicting results were observed in the glucose parameters. CONCLUSIONS: The potential for this glyburide—aspirin interaction resulting in a transient hypoglycemia should be considered in diabetic patients receiving glyburide therapy.

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.

The Family Practitioner-Clinical Pharmacist Group Practice—A Model Clinic

The establishment, organization, and operation of a pharmaceutical component within a primary care facility is delineated. This setting allows the pharmacist an opportunity to provide innovative clinical services. A mechanism of reimbursement is suggested which rewards the pharmacist for performing functions not directly related to the dispensing activity. The indications are that this arrangement could be financially feasible for a group practice including a pharmacist and one or two physicians.

Pharmacokinetics of single-dose erythromycin in normal and alcoholic liver disease subjects.

Six normal males and eight male subjects with alcoholic liver disease (ALD) and ascites were given a single 500-mg dose of erythromycin base. Twelve serum samples were collected at 0, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, and 24 h after dosing and assayed microbiologically for erythromycin concentration. Absorption was characterized by a zero-order model for both groups. ALD subjects demonstrated a shorter lag time (2.0 versus 3.0 h), an earlier peak (4.6 versus 6.3 h, P less than 0.05), and higher peak concentrations (2.04 versus 1.50 micrograms/ml) than normal subjects. Previously unreported biphasic elimination kinetics after oral dosing were observed in five and four ALD subjects. In the ALD group, the mean half lives for the first (alpha) and terminal (beta) phases were 1.6 and 4.5 h, respectively, and in normal subjects, were 1.3 and 6.6 h. The difference in alpha between groups was significant, P less than 0.05. The clinical significance of this finding for ALD patients receiving prolonged courses of erythromycin is discussed.