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Rectal absorption of methylprednisolone acetate and oral absorption of methylprednisolone and methylprednisolone acetate were investigated in a single-dose 3-way crossover study of 12 normal male volunteers. The median value of bioavailability (relative to oral dose) of methylprednisolone acetate based on unchanged methylprednisolone plasma levels was 14.2% after rectal administration, suggesting that the drug exerts its therapeutic effect topically rather than systemically. In contrast, the median of total radioactivity in urine (as a percentage of rectal dose) was 34.3% (range, 4.52% to 58.8%), suggesting partial bacterial metabolism in the rectum prior to absorption. Mean bioavailability (relative to oral administration of methylprednisolone acetate) of methylprednisolone after oral administration was 89.9%, indicating somewhat better systemic availability of the ester than the alcohol. The average apparent elimination rate constant for methylprednisolone after oral administration of both ester and alcohol was 0.290 hr-1, corresponding to a half-life of 2.39 hr.

Cardiovascular and hormonal responses to a structured interview, an electronic video game, a cold pressor test, and exercise on a bicycle ergometer were assessed in eighty-three 25- to 44-year-old normotensive Black and White men and women. Blacks showed significantly greater diastolic blood pressure (DBP) responses than Whites during the cold pressor test, which were not accounted for by an increase in plasma catecholamines. Exercise produced reliably greater systolic blood pressure (SBP) increases in Black women than in Black men or White women. Men showed significantly greater SBP and DBP changes than women during the video game. These findings suggest that the pattern of physiological reactivity elicited by challenge is related to the race and sex of the subjects.

Ranitidine is a potent histamine H2-receptor blocker that inhibits histamine- and pentagastrin-induced gastric acid secretion. After doses of 100 mg both intravenously and orally ranitidine kinetics and bioavailability were investigated in a single dose two-way crossover study in 12 normal men. Serum concentrations of ranitidine were determined by radioimmunoassay and urine concentrations by an ion-pair HPLC method. Intravenous data were fitted to exponential equations with the computer program NONLIN; model-independent kinetic parameters were calculated. Elimination t 1/2, plasma clearance, renal clearance, hepatic clearance, and volume of distribution for ranitidine after intravenous injection were 2 hr, 10.4 ml/(min X kg), 7.2 ml/(min X kg), 3.1 ml/(min X kg), and 1.82 l/kg, respectively; after oral doses mean t 1/2 was 2.7 hr and mean bioavailability was 52%. The average cumulative urinary excretion of ranitidine as percent of dose was 69.4 +/- 6.1% and 26.7 +/- 7.2% after intravenous and oral doses.

Blood ethanol concentrations were determined in 7 subjects during and subsequent to a 2-hr constant-rate intravenous infusion of ethyl alcohol (8% v/v). Eight to 10 capillary blood samples were collected during the infusion and 10 to 21 samples were obtained after the infusion ceased. Thus, the total time course of blood ethanol concentrations in man was defined, both during and postinfusion. Blood ethanol concentration data from each of 6 subjects were fitted simultaneously to the two equations for the one-compartment open model with zero order input and Michaelis-Menten elimination kinetics. The average Vm[0.232 mg/(ml x hr)] and Km[0.0821 mg/ml] obtained fron these fittings correspond very closely with corresponding values estimated by the fitting of all the mean concentration-time data obtained following oral administration of 4 different doses of ethanol to 8 other fasting subjects in another study. A disproportionate increase in area under the concentration-time curve with increase in dose (gm/kg) was observed in a single subject who was infused with equal volumes of a 4% and an 8% (v/v) ethanol solution at the same constant rate.

Plasma concentration-time data in man after oral dosing of the nonsteroidal antiinflammatory agent, tolmetin sodium, were fitted to both linear and nonlinear pharmacokinetic equations. The apparent elimination half-life of tolmetin is shown to be 4.5 to 6.0 hours. An analytical method is presented which allows measurement of plasma concentrations for at least 32 hr (compared with a previous limit of about 8 hr) after a single oral dose of the equivalent of 400 mg of tolmetin acid.

Two commercial prednisone tablets were studied which had previously been shown by Sullivan et al.5,6 to have the slowest and fastest in vitro rates of dissolution, and the slowest and fastest rise to peak plasma prednisolone concentrations in human beings. The effect of food on the adsorption of these two tablets was studied in a crossover study, which also repeated the fasting conditions used by Sullivan et al.6 Marked differences in mean prednisolone plasma concentrations during the 0- to 2-hour absorption phase were observed between the two tablets again, but food did not affect either tablet with respect to mean plasma prednisolone concentrations.

A novel method for detecting and quantitating pharmacokinetic drug-drug interactions is described. The method involves perturbation of an existing steady-state whole blood (or plasma) concentration of one drug by the other drug. The method would allow differentiation of "pharmacokinetic" drug interactions from "pharmacologic" interactions. It is shown that a bolus intravenous injection of propranolol reduced a steady-state arterial blood concentration of ethyl alcohol by 26% in the cat.

The pharmacokinetics of ranitidine were studied in ten patients with renal failure (creatinine clearance, 6-54 mL/min) after intravenous (IV) (50 mg) and oral doses (150 mg). After oral administration, peak plasma concentrations of 378-808 ng/mL were obtained in two to six hours. Plasma concentrations declined very slowly and concentrations greater than 100 ng/mL were obtained for 16 to 20 hours after the dose. The elimination half-life following oral administration was 8.5 +/- 2.8 hours (standard deviation [SD]), and the bioavailability of ranitidine was 43.3% +/- 10.5%. After IV administration, the elimination half-life, plasma clearance, renal clearance, and volume of distribution were 7.0 +/- 1.0 hours, 170 +/- 38 mL/min, 36.0 +/- 25.0 mL/min, and 1.3 +/- 0.4 L/kg, respectively. About 20% of the IV dose and 9% of the oral dose were recovered unchanged in urine. There was a significant correlation between the renal clearance of ranitidine and creatinine clearance (r = .74, P less than .05) after IV administration. The elimination half-life in patients with renal insufficiency is about three times greater than that reported in the literature for healthy subjects. Similarly, the plasma clearance in these patients is about 20% of that reported in healthy subjects. The results indicate that ranitidine elimination is appreciably reduced in renal failure and that an adjustment of dose in patients with renal failure is warranted. A dose of 75 mg bid may be adequate in maintaining the therapeutic plasma concentrations that are required for adequate H2-blocking activity.

The bioequivalence and absorption kinetics of naproxen in a new controlled-release tablet (750 mg or 1,000 mg naproxen) administered once daily were determined relative to an equivalent dose of the conventional naproxen tablet (375 mg or 500 mg naproxen) administered q12h. Naproxen was well absorbed from the controlled-release tablet (about 90%) compared with the conventional tablet. Absorption was dependent on drug release from the tablet matrix. The mean absorption time of naproxen averaged 8.4 hours for the 750-mg controlled-release tablet and 9.2 hours for the 1,000-mg controlled-release tablet. Once-daily administration of the controlled-release tablet resulted in equivalent trough concentrations of naproxen, and steady-state plasma concentrations were maintained within narrower limits than with twice-daily naproxen.

The antihypertensive and lipid effects of doxazosin and atenolol were compared in a 10-week, double-blind, parallel, placebo-controlled study. The 129 adults enrolled had mild to moderate hypertension (average supine diastolic blood pressures for doxazosin, atenolol and placebo were 100.6, 101.0 and 99.7 mm Hg, respectively). Patients were randomly assigned to treatment with doxazosin, 1 to 16 mg daily, atenolol, 50 to 100 mg daily or placebo. Among 114 patients included in the efficacy analysis, standing blood pressure (systolic/diastolic) changed by -13/-11 mm Hg with doxazosin (n = 37), -12/-12 mm Hg with atenolol (n = 39) and +1/-1 mm Hg with placebo (n = 38). Mean reductions in blood pressure for doxazosin and atenolol were significantly greater than those for placebo (p less than 0.01), although no statistically significant differences between the active agents were noted. Serum lipid measurements were evaluable for 116 patients, and the 38 doxazosin-treated patients in this group experienced reductions in total cholesterol, total triglyceride and very low density lipoprotein cholesterol levels. Both doxazosin and atenolol demonstrated comparable acceptance profiles. Doxazosin is an effective hypotensive agent with beneficial effects on serum lipid levels.

This double-blind, placebo-controlled, four-period cross-over study was undertaken to evaluate the sustained-release characteristics of long-acting propranolol hydrochloride (Inderal LA, Ayerst Laboratories, New York, NY) 60 mg qd, to compare the pharmacokinetic and pharmacodynamic properties of this formulation with conventional propranolol 20 mg tid, and to evaluate the proportionality of long-acting propranolol 60 mg (LA 60 mg) and long-acting propranolol 80 mg (LA 80 mg). Pharmacodynamic effects were evaluated in 34 healthy subjects by assessing heart rate, systolic blood pressure, and the product of heart rate and systolic blood pressure (double product) after exercise-induced tachycardia following both acute (day 1) and steady state (day 4) drug administration. The Cmax following administration of LA 60 mg was 9.5 and 11.4 ng/mL on days 1 and 4, respectively, compared with 18.8 and 20.0 ng/mL with 20 mg tid (P less than .0001). The tmax for LA 60 mg was significantly later (P less than .0001) than for conventional propranolol. Additionally, the apparent plasma half-life was significantly longer (P less than .0001) than with conventional propranolol. The LA 60-mg formulation was dose proportional to the LA 80-mg formulation. Pharmacodynamic evaluations showed no significant differences between LA 60 mg and 20 mg tid at any times tested with either acute or steady state dosing. This study demonstrates that LA 60 mg displays characteristics of a sustained-release formulation, is proportional with LA 80 mg, and produces pharmacodynamic effects that are similar to 20-mg tid dosing.

Forty-five ml of 95% alcohol, diluted to 150 ml with orange juice, was taken orally by six adult male volunteers under the following conditions: A (fasting), B (following a light breakfast), C (following a heavy breakfast), D (following a steak meal), E (alcohol 1 hr after a heavy breakfast), and F (alcohol 1 hr before a heavy breakfast). Using treatment A as a reference, the average area under the blood alcohol, time curve was reduced by 36, 63, 55, 56, and 18% for treatment B through F, respectively. The reduction in area is attributed to two factors: (a) food reduced the efficiency of absorption of alcohol; and (b) food reduced the rate of absorption of alcohol, which, coupled with the operation of Michaelis-Menten elimination kinetics, contributed to the reduction in area. The latter effect is a result of changes in the ratio: instantaneous rate of metabolism/amount of alcohol in the body, which results in a smaller area when the rate of absorption is slow than when the rate of absorption is rapid. Using treatment A as a reference, the ratio of the average peak alcohol concentrations were: 1.0, 0.72, 0.35, 0.50, 0.49 and 1.11 for treatments A through F, respectively.

The pharmacokinetics of ranitidine and its removal by hemodialysis were determined in 9 patients with chronic renal failure requiring hemodialysis. Ranitidine (50 mg) was administered as an intravenous bolus at the beginning of the dialysis procedure, which lasted for 4 h. The elimination half-life, plasma clearance and volume of distribution (VD area) of ranitidine in these patients were 9.0 +/- 2.6 h (mean +/- SD), 305 +/- 152 ml/min and 3.5 +/- 1.9 liters/kg, respectively. About 8% of the administered dose was removed during a single dialysis procedure. The elimination of ranitidine is appreciably reduced in these patients. These results suggest that the dose of ranitidine should be adjusted in patients with severe renal failure who are undergoing hemodialysis, and a suitable schedule for dosing such patients is suggested.

Etodolac, a new anti-inflammatory analgesic drug found to be effective in treating arthritis in a dose range of 100 to 300 mg bid, has been shown to induce significantly less gastrointestinal microbleeding in normal men than several other NSAIDs. In this study, the effect on gastrointestinal blood loss of high-dose etodolac, 300 and 500 mg bid, versus piroxicam at its normal therapeutic dose of 20 mg qd, was investigated by the 51Cr method in 23 men with osteo- or rheumatoid arthritis. Placebo periods preceded and followed 28 days of active drug treatment. Blood and stool analyses were performed by an analyst not aware of drug assignment or study design. Patients receiving piroxicam, but not those receiving either dose of etodolac, had a significantly higher mean level of fecal blood loss in the active treatment phase compared with the pretreatment placebo level (p less than 0.01). Further, microbleeding was significantly greater for the piroxicam group during treatment than for either of the etodolac groups (p less than 0.01). There were no significant differences in fecal blood loss between the two groups receiving etodolac compared with pretreatment. Even at doses two to three times those found effective in the treatment of arthritis, etodolac produces no increase in fecal blood loss, in contrast to blood loss seen with the recommended dose of piroxicam. Fecal blood loss in osteoarthritic patients, not receiving an NSAID, was similar to normal subjects in previous studies.

In eight experiments involving four cats, doses of 12.5 to 50 mg of sodium pentobarbital per kg of body weight were administered intravenously and pentobarbital plasma concentrations (from arterial blood) were measured as a function of time. Pharmacokinetic linearity was evidenced by a mean plasma clearance (C1p) of 1.81 ml/(kg x min), with a coefficient of variation of 16.6%, and a range of 1.51 to 2.36 for all experiments, and, a linear relationship between total area under the curve (AUC) and mg/kg dose in cat "4 given doses of 12.5, 25 and 50 mg/kg. However, the apparent elimination half-life, (t1/2)beta' averaged 4.87 hr, with a coefficient of variation of 40.7%, and range of 1.80 to 7.52 in all experiments, and, in cat "4 the half-life was the same, namely 7.5 hr following the two higher doses, but lower, namely 4.7 hr, after the lowest dose. There was also evidence of kinetic nonlinearity in the intial fall-off portions of some of the curves. Results are compared with literature data for both rabbits anamen. The order of plasma clearances in units of ml/(kg x min) were: rabbit greater than cat greater than man. For neither the rabbit nor the cat were there any significant correlations between calculated pharmacokinetic parameters and mg/kg doses using data from all animals studied; this also suggests kinetic linearity.

Sodium fluoride (6--8 mg/ml) inhibits hydrolysis of methylprednisolone acetate to methylprednisolone. An HPLC method for simultaneous determination of hydrocortisone, methylprednisolone and methylprednisolone acetate in plasma is presented. Analysis of plasma samples (containing NaF) for methylprednisolone acetate shows no significant change in concentration over extended periods of storage at -20 degrees C. In vitro hydrolysis of methylprednisolone acetate at 37 degrees C in human whole blood is rapid (average t1/2 = 19 min). In one cat, the bioavailabilities of methylprednisolone acetate rectally was 13% and of methylprednisolone (alcohol) rectally was 26%, relative to intravenous administration of methylprednisolone. In the same cat, the bioavailabilities of methylprednisolone acetate orally was 93% and of methylprednisolone was 82%, relative to intravenous administration of methylprednisolone. All samples collected after oral administration of methylprednisolone acetate to a human subject were found to contain only methylprednisolone (alcohol) indicating hydrolysis of the drug during absorption through the gastrointestinal membrane and/or in the liver. If the ester had the same half-life in blood in vivo as measured in vitro, it would have been measurable in plasma.

The antihypertensive effect of doxazosin 1-16 mg once-daily was compared with that of atenolol 50-100 mg once-daily, and placebo, utilizing a double-blind parallel group (12 patients each) design. Blood pressure (BP) and pulse rate were determined in out-patients who returned for clinic visits every 2 weeks for 14 weeks. During the first 4 weeks, all patients received single-blind placebo therapy. During the subsequent 10 weeks, patients were randomized to placebo, atenolol or doxazosin treatment. After 2 weeks of doxazosin therapy 16 mg daily, there was a significant decrease from baseline (single-blind placebo period) in supine diastolic BP (P less than 0.01) and standing diastolic BP (P less than 0.001). The decreases in supine and standing diastolic BPs in the doxazosin 16 mg daily group were significantly (P less than 0.01) different from the corresponding BPs of the placebo group. At weeks 12 and 14, heart rates in the doxazosin group were not significantly different from baseline or from those in the placebo group. After 4 and 6 weeks of atenolol 100 mg daily, there was a significant decrease from baseline in both supine (P less than 0.001 and P less than 0.05) and standing (P less than 0.05) diastolic BPs and heart rates (P less than 0.05). However, when the atenolol group was compared with the placebo group, a significant decrease occurred only with supine diastolic BP at week 12 (P less than 0.01) and not at week 14; but significant decreases occurred in supine and standing heart rates at weeks 12 and 14 (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

The reproducibility of drug absorption within a given subject as well as the evaluation of bioavailability of two digoxin dosage forms were studied. The data showed (a) a higher initial plasma digoxin concentration after the soft elastic gelatin (SEG) capsule; (b) a more irregular absorption after the tablet; (c) on the average, the coefficients of variation of individual plasma concentrations were lower after the capsule; and (d) for the capsule, the intrasubject variations of the peak plasma concentrations, time of peak, area under plasma concentrations-versus-time curve (AUC), and amount digoxin excreted in urine (Ae) were on the average 60 per cent of the variations in the tablet parameters. The ratios of AUC and Ae for capsule/tablet were essentially unity, indicating that the amount digoxin absorbed from the 0.4-mg digoxin SEG capsule is identical to that from a 0.5-mg standard reference tablet.

The effect of a kaolin--pectin suspension on the bioavailability of orally administered digoxin was evaluated when both drugs were given concomitantly and when their time of administration was separated by 2 hr. Coadministration of the antidiarrheal with the cardiac glycoside delayed absorption of the latter and, at the same time, decreased by 62% the amount of drug absorbed. Intersubject variation in digoxin bioavailability also was increased more than twofold. When the kaolin--pectin suspension was given 2 hr before the cardiac glycoside, the digoxin absorption rate was not affected, although its relative extent of absorption was reduced by about 20%. In contrast, when the antidiarrheal was given 2 hr after digoxin, neither the rate nor the extent of absorption of the cardiac glycoside was perturbed. No change in the intersubject variability in digoxin bioavailability was noted whether the antidiarrheal was given 2 hr before or 2 hr after the cardiac glycoside.

The relative degree of absorption of methylprednisolone acetate when administered by the rectal and oral routes was studied in 12 normal male subjects. The plasma samples were assayed for methylprednisolone and endogenous hydrocortisone concentrations. After the administration of equal doses of methylprednisolone acetate by the rectal and oral routes, the plasma hydrocortisone levels were not significantly different from each other; but the plasma concentrations of methylprednisolone were significantly lower after rectal administration than after oral administration. We conclude that the practice of utilizing the degree of suppression of endogenous hydrocortisone levels as an indicator of the extent of absorption of rectally administered glucocorticoids is inappropriate.

Twenty-five hypertensive patients participated in a randomized placebo-controlled study. After blood pressures were normalized with propranolol or verapamil alone over a 6-week period, patients were entered into a 4-week double-blind period where they received non-steroidal anti-inflammatory drug (NSAID) treatment (sulindac or piroxicam) or placebo treatment in addition to their antihypertensive therapy. There was a significant elevation in standing systolic blood pressure (P less than 0.05) with propranolol and sulindac, when compared with propranolol and placebo, but no significant changes were shown with propranolol and piroxicam. Systolic blood pressures on sulindac treatment were significantly lower (P less than 0.05) in both supine and standing positions during treatment of hypertension with verapamil compared with propranolol. Both supine systolic and diastolic blood pressures on piroxicam treatment were significantly lower (P less than 0.05) during treatment of hypertension with verapamil compared with propranolol. We conclude that NSAID transiently block the antihypertensive effect of propranolol, causing blood pressures to increase and side effects to improve. However, NSAID do not cause loss of antihypertensive control with verapamil.

The intrasubject and intersubject variabilities for CGS 16617, an angiotensin converting enzyme inhibitor, were evaluated in an open-label, repeat single-dose bioavailability trial. Eight healthy male volunteers each received a 20-mg oral dose of CGS 16617 as an aqueous solution on four separate occasions. Components of variance were evaluated for a mixed-effects statistical model in which subjects were regarded as a random factor. While intersubject variability was statistically significant (P less than 0.05) for all pharmacokinetic variables measured, AUC, Cmax, t1/2, and tmax, its contribution to the total observed variability was relatively small for AUC, t1/2, and tmax. The proportion of variation due to intrasubject variability was 70, 19, 61, and 72% for AUC, Cmax, t1/2, and tmax, respectively. Ramifications of the large intrasubject source component of variability as related to bioavailability trials and biological variation are discussed.

Generalizability theory was used to examine the stability of blood pressure (BP) measurement in normotensives and mild hypertensives. Three to six readings at home or at work provided adequate reliability for the same day in each setting. Under structured laboratory conditions, two to three BP measures taken on each of 2 to 3 days for systolic and diastolic BP provided conservative estimates that were generalizable across days. Finally, generalizations across settings called for five or more measurements taken in at least two settings.

Digoxin doses of 14.3, 5.72 or 1.43 mcg/kg were administered to 8 cats and the plasma digoxin concentrations (concns) were measured as a function of time for 96 hr. Pharmacokinetic linearity was evidenced by: (1) mean plasma clearance (Clp) of 4.05 ml/(kg x min) with a coefficient of variation of 34.6% and a range of 2.69-6.71; (2) linear relationship between total area under the plasma concn-time curve and the administered dose. Further evidence for linearity was the lack of dose-dependence of apparent elimination half-life (beta). The volume of distribution and beta for cats were respectively (mean +/- s.d.) 20.4 +/- 5.35 L/kg and 0.0120 +/- 0.0030 hr-1. Results from cats were compared with literature data for dogs and man. The order of Clp in units of ml/(kg x min) were: infant greater than dog greater than cat greater than adult man.