Ranitidine bioavailability and kinetics in normal male 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.

Rectal and oral absorption of methylprednisolone acetate.

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.

Pharmacokinetics of ranitidine following oral administration with ascending doses and with multiple-fixed doses.

The aim of these studies was to further delineate pharmacokinetic characteristics of ranitidine, a new histamine H2-receptor antagonist. In one study, ranitidine was administered orally to six normal men in increasing doses of 100 mg, 150 mg, 250 mg, and 400 mg weekly over a four-week period. The peak serum concentrations increased with the corresponding increases in dose but the time needed to reach peak serum concentration did not vary significantly with increased doses. The pharmacokinetic parameters were calculated for each subject at each of the four dose levels. The total area under the curve (AUC) at the four different doses was linearly related to the dose for each individual subject; and a plot of AUC versus dose had a correlation coefficient of .886 (P less than .001). The apparent plasma clearance did not vary with the increase in dose; and the average corrected clearance values ranged between 6.7 and 10 mL/(min X kg). Elimination half-life was between 2.6 and 3.0 hours; and the volume of distribution (Vd area) was between 1.6 and 2.4 L/kg. About 35% of the ranitidine dose was excreted in the urine in the unchanged form over a 12-hour excretion interval. In the second study, ranitidine was administered orally to 12 normal subjects in doses of 150 mg and 200 mg twice daily for 28 days. The pharmacokinetic parameters for ranitidine with multiple-dose treatment were similar to those obtained with single-dose administration. Predose ranitidine concentrations (trough levels) did not increase with multiple dose administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Efficacy and pharmacokinetics of oral pirmenol, a new antiarrhythmic drug.

Pirmenol is a new orally effective antiarrhythmic agent. Reported are the results of oral administration of pirmenol to six patients (age 48.5 +/- 8.6 years, weight 83 +/- 15 kg) with stable ventricular extrasystoles (PVCs)--average ectopy rate 1040 +/- 630/hr (mean +/- SD). Patients received oral doses of placebo or 200 mg of pirmenol in a double-blind cross-over fashion followed by a single-blind rising-dose administration of 250 mg and 300 mg of pirmenol. The time period between doses was 48 hours. Pirmenol was rapidly absorbed (time to peak plasma levels 1 to 1.5 hours) and the mean maximum plasma concentrations were 1.8, 2.7 and 3.4 micrograms/mL with 200-mg, 250-mg and 300-mg doses, respectively. The elimination half-life was 9.3 +/- 3.0 hours and 31 +/- 14% of the dose was recovered in urine. The response criterion (80% suppression of PVCs of control for 8 hours) was met after the 300-mg dose in three patients. In three patients greater than 80% reduction occurred for up to 8 hours after the 200-mg dose. Pirmenol administration was not associated with any significant changes in blood pressure, heart rate, hepatic and renal function, PR interval or QRS duration. LV ejection fraction determined echocardiographically decreased from 63.0 +/- 6.9% predose to 59.7 +/- 5.0% about 2 hours after the 300-mg dose and QT interval increased by less than 10%. Two patients complained of transient bad taste sensation. Our results suggest that 250 mg to 300 mg of pirmenol, administered twice a day will suppress the PVCs effectively.

Pharmacokinetics of single-dose oral and intramuscular ketorolac tromethamine in the young and elderly.

The elderly are likely candidates to receive analgesics for pain from a variety of etiologies. Ketorolac tromethamine is a nonsteroidal, analgesic, anti-inflammatory, antipyretic investigational drug with anti-prostaglandin synthetase activity. Sixteen healthy, young men (mean age 30 years and mean weight 75 kg) and 13 healthy, elderly subjects (11 men and two women; mean age 72 years and mean weight 75 kg) participated in an open-label, parallel single-dose study. On each day of ketorolac tromethamine administration the subjects fasted overnight and for 2 hours post-dose. A single intramuscular (IM) dose of 30 mg of ketorolac tromethamine was administered followed by an oral dose (PO) of 10 mg after a 1 week washout period for the elderly subjects. Plasma samples were taken from 0 through 48 hours post-dose and analyzed for ketorolac by HPLC. The elimination of ketorolac was decreased slightly in the elderly following both doses, as evidenced by a prolongation in half-life (4.7 to 6.1 hours for PO and 4.5 to 7.0 hours for IM) and a reduced total plasma clearance compared to the young adult subjects. These differences were statistically significant (P less than .001). Considerable overlap frequently was observed when comparing the range of values obtained for the young and elderly for plasma half-life, clearance, AUC, Tmax and Cmax. The absorption of ketorolac tromethamine was not altered substantially in the elderly following either dose route. Ketorolac plasma protein binding was not altered substantially in the elderly. The present results show that the elderly may need slightly less frequent dosing of ketorolac than young adults to maintain similar plasma levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of cefprozil in healthy subjects and patients with hepatic impairment.

The pharmacokinetics of cefprozil were studied in 12 (9 men, 3 women) subjects with hepatic impairment and in 12 healthy subjects who were matched for age, sex, and weight. Each subject received a single 1000 mg oral dose of cefprozil, which consists of cis and trans isomers in approximately a 90:10 ratio. Serial blood and urine samples were collected and analyzed using validated HPLC/UV methods for the concentration of each isomer. The results of the plasma and urine analyses were subjected to noncompartmental pharmacokinetic analysis. The values for the peak plasma concentrations (Cmax), area under the plasma concentration versus time curve (AUC0-infinity), apparent total body clearance (Clt/F), renal clearance (Clr), and percent of drug excreted in urine (%UR) of each isomer were not significantly different in healthy subjects and patients with hepatic impairment. The only parameters that were significantly (P less than or equal to .05) longer in patients with hepatic impairment were mean residence time in the body (MRT) and half-life; the MRT for the cis isomer in healthy subjects and subjects with hepatic impairment were 3.33 hr and 3.88 hr, respectively, and for the trans isomer 3.17 hr and 3.68 hr; the half-life for the cis isomer was 1.62 hr and 2.22 hr, respectively, and for the trans isomer 1.21 hr and 1.54 hr. The pharmacokinetics of the cis and trans isomers of cefprozil were virtually identical in healthy subjects as well as those with hepatic impairment.

A multiple-dose pharmacokinetic comparison of naproxen as a once-daily controlled-release tablet and a twice-daily conventional tablet.

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.

Cardioselectivity of cetamolol compared with atenolol and nadolol.

The selectivity of the beta-adrenoceptor blockade produced by single oral doses of cetamolol, atenolol, and nadolol was compared in normal male subjects. Study 1 established the dose at which each drug provides equivalent beta-1 blockade. Beta-1 blockade was estimated using the degree of inhibition of the increased heart rate (HR) response to graded exercise. Cetamolol (30 mg), atenolol (100 mg), and nadolol (80 mg) all attenuated the HR response to a comparable extent. This result established that the dose ratio of cetamolol:atenolol:nadolol of 1.00:3.33:2.67 provides equipotent beta-1 blockade. This ratio of doses was used in Studies 2 and 3 to evaluate the antagonism of beta-2-mediated responses to titrated doses of intravenous isoproterenol (ISO) by low and high doses of each drug. Beta-2 blockade was assessed using the attenuation of ISO-induced reductions in diastolic blood pressure (DBP) in Study 2 and ISO-induced increases in specific airway conductance (sGAW) in Study 3. For within drug comparisons, antagonism of the HR increase induced by ISO (a response mediated by both beta-1 and beta-2 receptors) was also examined. Treatments included cetamolol (15 and 60 mg), atenolol (50 and 200 mg), and nadolol (40 and 160 mg in Study 2; 40 mg only in Study 3). All drugs tested suppressed the HR, DBP, and sGAW responses to ISO, and this blockade was dose dependent. Cetamolol and nadolol produced approximately equipotent beta-1 blockade, whereas cetamolol at both doses produced a less potent beta-2 blockade. Atenolol antagonized ISO effects on all parameters less than either cetamolol or nadolol. Quantitative cardioselectivity indices revealed that cetamolol 60 mg was the most cardioselective and nadolol 40 mg the least. Data from the three studies demonstrate that cetamolol is cardioselective relative to nadolol and that, in contrast to atenolol, cardioselectivity appears to increase at the higher dose.

Pharmacokinetics and pharmacodynamics of long-acting propranolol 60-mg capsules: a comparative evaluation.

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.

Fluconazole penetration into cerebrospinal fluid in humans.

One hour after intravenous doses of 50 mg/d fluconazole for 6 days or 100 mg/d for seven days to healthy subjects, the cerebrospinal fluid concentrations of fluconazole were 1.26 mg/L and 2.74 mg/L, respectively. These values were approximately 52% and 62% those of serum. Four patients with an initial clinical diagnosis of meningitis also had significant concentrations of fluconazole in the cerebrospinal fluid.

Comparative pharmacodynamics and pharmacokinetics of conventional and long-acting propranolol.

This investigation was conducted to compare the pharmacokinetic and pharmacodynamic effects of single and multiple doses of conventional propranolol and long-acting propranolol in healthy human volunteers. Two double-blind, randomized, double-crossover, Latin square studies were carried out. One study evaluated long-acting propranolol 160 mg/d, conventional propranolol 40 mg qid, or placebo for seven days in 24 men. The other study compared long-acting propranolol 80 mg/d, conventional propranolol 20 mg qid, or placebo for seven days in 27 men. At specific times after the administration, blood samples were obtained, and heart rate and blood pressure were measured; exercise tests were done both on the first day and at steady state (day 7). In both studies, the area under the plasma propranolol concentration-time curve and the peak concentration were significantly less (P less than .0001) after the administration of long-acting propranolol compared with conventional propranolol on both day 1 and day 7; in addition, the elimination half-life was longer after administration of the long-acting preparation (9 hr) compared with that following the conventional dosage form (4 hr). Both conventional and long-acting propranolol significantly decreased the exercise heart rate at each of the selected time points (P less than .05) compared with placebo. Reduction in exercise heart rate was greater with conventional propranolol than with the long-acting formulation, but the differences were not statistically significant, when exercise was performed only at trough levels of the conventional drug. The decreases in exercise heart rate were correlated with plasma propranolol concentrations.

Pharmacokinetics of ranitidine in patients with renal failure.

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.

Dose-ranging study to delineate the additive antihypertensive effect of guanabenz and captopril.

This open crossover study in eight hypertensive patients defined a possible additive effect of oral guanabenz and captopril and determined a safe and effective dose range. Each group of four patients received placebo followed by ascending doses (on alternate days) of either guanabenz (2, 4, 8 mg) or captopril (6.25, 12.5, 25 mg) as initial monotherapy and were subsequently crossed over to the alternate monotherapy. Guanabenz and captopril were given concomitantly in increasing doses--the highest dose for both groups being 8 mg guanabenz/25 mg captopril. When guanabenz and captopril were given concomitantly, blood pressure decreased, both from the values during placebo administration and from the lead-in values recorded before each dose. Mean supine systolic and diastolic blood pressures after combination therapy decreased significantly (P less than .05) in a dose-related manner at most evaluations. The authors conclude that guanabenz and captopril have an additive effect when administered in combination to patients with hypertension.

Gastrointestinal blood loss in arthritic patients receiving chronic dosing with etodolac and piroxicam.

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.

Determination of methylprednisolone and hydrocortisone in plasma using high pressure liquid chromatography.

A method for quantitative determination of methylprednisolone and hydrocortisone in plasma using added methylprednisolone acetate as internal standard and high pressure liquid chromatography is presented. The standard curves were evaluated statistically and logarithmic parabolic equation is preferred over the usual standard curve mathematical relationships. The method was applied to samples of one subject's plasma containing methylprednisolone and endogenous hydrocortisone after oral dosing with multiple doses of methylprednisolone.

Dose-response relationship of single oral doses of guanabenz in hypertensive patients.

A single-blind, placebo-controlled study was conducted to determine the dose-response relationship of guanabenz, administered as single oral doses to patients with mild or moderate hypertension. Twelve hypertensive patients received ascending oral doses of 2, 4, 8, 16, 24, and 32 mg of guanabenz. Dose-response relationships were evaluated for the nine patients who received placebo and all six guanabenz doses. The greatest maximum response (40/24 mm Hg) was seen for the 16 mg guanabenz dose. Since eight of the nine patients had mild hypertension, they may have responded maximally to the lower guanabenz doses, precluding larger decreases with the 24 and 32 mg doses. The mean onset of satisfactory blood pressure reduction decreased from 4 to 2 h and the mean duration increased from 6 to 22 h as the oral dose was increased from 2 to 32 mg. In eight patients, the responses to 16 mg of guanabenz administered sublingually and orally were compared. The sublingual and oral routes produced similar mean (20/13 mm Hg) and maximum (33/24 mm Hg) blood pressure decreases as well as mean onset (2 h) and duration (16.5 h) of satisfactory response. Additional studies involving patients with more severe hypertension are needed to further characterize the dose-response relationship of oral guanabenz and to establish a dose-response relationship for sublingual guanabenz.

Pharmacokinetics of thiopental in the asphyxiated neonate.

The pharmacokinetic properties of thiopental were studied in 10 asphyxiated neonates (mean +/- SE; birth weight, 3,244 +/- 212 g; gestational age, 40 +/- 1 weeks) as part of a randomized, controlled trial which tested the ability of barbiturate therapy to decrease central nervous system damage secondary to perinatal asphyxia. Therapy was begun at a mean age of 2.3 h in all and was initially given as a loading dose of 15 mg/kg over 30 min followed by a constant infusion. The mean steady-state thiopental concentration was 13.4 +/- 3.7 micrograms/ml (mean +/- SD) and the average time to reach steady state was 7 +/- 5 h. Mean elimination half-life, plasma clearance and volume of distribution for thiopental were 39 h (range 26-70), 66 ml/(h x kg) (range 31-172), and 3.6 liters/kg (range 1.1-6.7), respectively. Arterial blood pressure support was required in 8 of 10 patients. While it appears feasible to give thiopental to the asphyxiated neonate at the reported infusion rates, the risk-benefit ratio is increased by the frequent associated hypotension and need for pharmacologic blood pressure support.

Preliminary in vitro and in vivo investigations on methylprednisolone and its acetate.

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.

Pharmacokinetics of propranolol in the cat and comparisons with humans and three other species.

The aims of this study were to describe the pharmacokinetics of propranolol in the cat, to compare pharmacokinetic parameters for propranolol in the cat with those of four other species and to apply the two-step infusion method of Wagner (Clin. Pharmacol. Ther. 16, 691-700, 1974) in order to attain a rapid steady-state level for propranolol in plasma. Seven healthy adult cats received propranolol either as an I.V. bolus or by the two-step I.V. infusion method. The latter method was very effective in rapidly attaining and maintaining steady-state plasma propranolol levels. Pharmacokinetic parameters for propranolol in the cat are as follows: plasma clearance, 31.3 ml/(kg x min); volume of distribution, 1.57 L/kg; elimination half-life, 35 min. When compared with other species, the order of plasma clearances for propranolol were: rat greater than dog greater than cat greater than man greater than monkey. A plot of total area under the plasma propranolol concentration-time curve versus dose was not linear at the lower doses, but was linear at doses greater than 0.242 mg/kg.