Chiral kinetics and dynamics of ketorolac.

It has been shown that the analgesic and cyclooxygenase inhibitor activity of ketorolac tromethamine (KT), which is marketed as the racemic mixture of (-)S and (+)R enantiomers, resides primarily with (-)S ketorolac and that the ulcerogenic activity of this agent also resides in (-)S ketorolac. Resolution of individual enantiomers for analysis in plasma samples has been accomplished by two methods: derivatization to form diastereomers that are separated by HPLC, or direct HPLC using a chiral phase column. When mice and rats were given oral solutions of (-)S and (+) KT, it was found that the kinetics and interconversion of the enantiomers were species and dose dependent. Interconversion was higher in mice than in rats; when (-)S KT was administered, 71% of the area under the concentration-time curve (AUC) was due to (+)R ketorolac in mice, compared with 12% in rats. More interconversion was observed at higher doses; the percent of AUC due to (-)S ketorolac when (+)R KT was administered increased from 12% to 25% in mice and from 2% to 8% in rats. In general, more interconversion occurred from (-)S to (+)R ketorolac in the animal studies. Human subjects were given single oral solution doses of racemic KT (30 mg), (-)S KT (15 mg), and (+)R KT (15 mg). The plasma concentrations of (-)S ketorolac were lower than (+)R ketorolac at all sample times after racemic KT (22% of the AUC was due to (-)S ketorolac). When (+)R KT was administered, (-)S ketorolac was not detectable and interconversion was essentially 0%. When (-)S KT was administered, significant levels of (+)R ketorolac were detectable and interconversion was 6.5%. After all doses, plasma half-life was shorter and clearance greater for (-)S ketorolac than for (+)R ketorolac. Thus, in humans very little or no interconversion of (+)R to (-)S was observed, and interconversion of (-)S to (+)R was minimal (6.5%). These data demonstrate that the kinetics and interconversion of the enantiomers of ketorolac is different in animals and humans as well as from most other NSAIDs. This may be due to more rapid excretion or metabolism of (-)S ketorolac and a different mechanism of interconversion.

Tolerability, central effects and pharmacokinetics of intravenous ketorolac tromethamine in volunteers.

The central effects, tolerability and pharmacokinetics of multiple intravenous doses of the analgesic ketorolac tromethamine (30 mg 4 times daily for 5 days) were studied in male volunteers. In this double-blind, randomized, parallel group study, 13 subjects received ketorolac tromethamine and 7 subjects received placebo (vehicle). To determine the effects of withdrawal all subjects were then given further dosing with placebo (4 times daily) for 2 days while maintaining the double-blind nature of the previous drug assignment. Physical examinations and laboratory tests were obtained prior to the drug administration and after completion of the study. Scales for assessment of anxiety, depression, sleep and opiate withdrawal were presented to the subjects on day 2, 5, 6, 7 and 8 of the study. After 5 days of multiple intravenous doses ketorolac showed overall good systemic tolerance and safety in comparison with placebo. Myalgia and taste perversion were more frequently reported in the ketorolac group. The frequency of injection site complaints, mostly transient pain, was about 80% for both ketorolac and placebo, indicating these were likely caused by the vehicle. There were no significant changes in the scales assessing anxiety, depression, sleep and opiate withdrawal during treatment with ketorolac and after its withdrawal, suggesting that the drug has neither any major central effects nor any clear addiction potential in this dose schedule. Pharmacokinetic parameters were derived from plasma samples collected after the first and last active doses.(ABSTRACT TRUNCATED AT 250 WORDS)

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)

Ketorolac tromethamine pharmacokinetics and metabolism after intravenous, intramuscular, and oral administration in humans and animals.

In humans, ketorolac is completely bioavailable and its kinetics are linear. It is absorbed rapidly (half-life for absorption 3.8 min) after oral (fasting) and intramuscular administration; food delays but does not reduce its absorption. The drug is highly protein bound in humans (greater than 99%). The mean plasma elimination half-life is 5-6 hours, and ketorolac is not extensively distributed outside the vascular compartment (Vd beta 15 L). Virtually all of the drug-related material circulating in plasma is in the form of ketorolac (greater than 96%), with the only metabolite the pharmacologically inactive p-hydroxyketorolac (PHK). Humans excrete about 90% of the administered dose in urine. About 60% of drug-related material recovered from urine is ketorolac, about 12% is PHK, and 28% represents polar, glucuronide conjugates of ketorolac. The animal models in which ketorolac's metabolism and kinetics are most similar to those in humans are the mouse and monkey, respectively.

Pharmacokinetics of norethindrone: effect of particle size.

In 24 healthy women between the ages of 19 and 35 years who had not used oral contraceptive preparations for at least 60 days, it was found that the smaller the particle size of norethindrone (NET) administered, the higher was the plasma NET level obtained. Three different preparations having particle sizes of NET smaller than 250 microns, 44 microns or 10 microns were tested in a crossover pattern. The time required to reach maximum plasma concentration (Tmax) became shorter with decreasing particle size, 1.69 hr, 1.52 hr and 1.06 hr, respectively. As particle size was reduced, the maximum NET plasma concentration (Cmax) increased for the 3 different 1 mg NET preparations, i.e. 8.66 ng/ml, 10.53 ng/ml and 15.73 ng/ml. A trial with a 2 mg NET preparation made with NET utilizing the 44 microns same material displayed a Tmax similar to the 1 mg NET preparation having the same particle size while the Cmax reached a level of 17.56 ng/ml. The area under the plasma concentration versus time curve from 0-24 hrs and the extrapolated total area under the curve, increased with decreasing particle size. The use of a smaller particle size allows for more rapid dissolution or oral contraceptive tablets when measured in vitro; however, there is no evidence that such faster dissolution leads to a significant difference in efficacy. Oral contraceptive tablets have, since their inception, utilized both large and small NET particle size material in various preparations.

Bioequivalence of two oral contraceptive drugs containing norethindrone and ethinyl estradiol.

Two oral contraceptive drugs, Formulation A and Formulation B, both of similar hormonal content, were compared with each other to determine if they were bioequivalent. Both drugs contain 1 mg of norethindrone (NET) and 0.035 mg of ethinyl estradiol (EE). Application of an interval test for the ratio of the computed parameter means demonstrated equivalence for the two formulations with respect to the 0-24 hour area under the plasma level versus time curve (AUC24), the total area under the curve (AUCtot) and for the maximum plasma concentration (Cmax) for both ethinyl estradiol and norethindrone. The data support the hypothesis for bioequivalence of the two formulations with respect to total absorption.

Pharmacokinetics of ketorolac and p-hydroxyketorolac following oral and intramuscular administration of ketorolac tromethamine.

Ketorolac tromethamine (KT), a potent analgesic with cyclooxygenase inhibitory activity, was administered in an open, randomized, single-dose study of Latin-square design to 12 healthy male volunteers. Doses of 30 mg oral (po) and 30, 60, and 90 mg intramuscular (im) KT were administered in solution. Plasma samples were analyzed for ketorolac (K) and its inactive metabolite, p-hydroxyketorolac (PHK), by reversed-phase high-performance liquid chromatography (HPLC). The 30-mg im dose was found to be similar to the 30-mg po dose with respect to total AUC values for both K and PHK. The amount of PHK circulating in plasma was very low as judged by AUC ratios (PHK/K x 100) of 1.9 and 1.5% for the 30-mg po and im doses, respectively. The rate of absorption of K and formation of PHK, as determined by Cmax and Tmax values, was significantly slower following the im doses. Total AUC and Cmax for K and PHK increased linearly with dose after im administration of 30, 60, and 90 mg of KT. The mean plasma half-life of K was remarkably consistent between po and im administration and was independent of dose, ranging from 5.21 to 5.56 hr. The plasma metabolic profile was similar following both routes of administration and graded im doses.

Absorption of naproxen controlled-release tablets in fasting and postprandial volunteers.

The absorption of naproxen in a new controlled-release (CR) formulation (1000 mg tablet) was studied in fasting and postprandial volunteers. The total area under the plasma concentration-time curve averaged 2221 micrograms.hr/mL in fasting participants and 2111 micrograms.hr/mL in postprandial participants; whereas the difference was statistically significant (P = .025), the 95% confidence intervals indicated equivalent values. The peak plasma concentration was lower in the fasting state (63.1 micrograms/mL) than in the fed state (86.1 micrograms/mL) (P = .0001). There were no statistically significant differences between fasting versus postprandial values for the mean absorption time (9.7 hr vs. 7.7 hr) or plasma half-life (17.3 hr vs. 17.6 hr). Hence, the rate and extent of absorption of CR naproxen was not substantially altered by the ingestion of food.

Pharmacokinetics of ketorolac tromethamine in humans after intravenous, intramuscular and oral administration.

The pharmacokinetics of ketorolac tromethamine, a potent non-narcotic analgesic agent used for relief of moderate to severe pain, has been studied in 15 healthy volunteers who received single 10 mg doses intravenously (i.v.), intramuscularly (i.m.) and orally (p.o.) in a three-way cross-over design. The kinetics of i.v. ketorolac were characterized by a terminal half-life of 5.09 h, a small plasma clearance (CL = 0.35 ml.min-1.kg-1) and a small tissue distribution (Vss = 0.11 l.kg-1, V beta = 0.17 l.kg-1; mean (SD). Following i.m. and p.o. administration, peak levels of approximately 0.8 microgram/ml were rapidly attained (tmax = 0.8 and 0.9 h, respectively) and the systemic bioavailability was essentially complete.

Ketorolac tromethamine absorption, distribution, metabolism, excretion, and pharmacokinetics in animals and humans.

Ketorolac tromethamine (KT), a potent non-narcotic analgesic, with cyclooxygenase inhibitory activity, was administered (14C-labeled and unlabeled) intravenously (iv), orally (po), and intramuscularly (im) in solution to humans, cynomolgus monkeys, rabbits, rats, and mice. KT was absorbed rapidly (Tmax less than 1.0 hr) and efficiently (greater than 87%) following po and im doses in all species. The plasma half-life of ketorolac (K) ranged from 1.1 hr (rabbits) to 6.0 hr (humans). The protein binding of K ranged from 72.0% (mouse) to 99.2% (humans). Linear pharmacokinetics of K was observed in the mouse after single oral doses of KT ranging from 0.25 to 16 mg/kg. Radioactivity was excreted predominantly into urine, ranging from 78.9% (mouse) to 102% (monkey) following iv doses. The dose was excreted into urine primarily as K conjugates, K, and p-hydroxy-K in humans. The monkey was similar to humans with respect to kinetics, but did not form the p-hydroxy metabolite. The rabbit was unusual in that it exhibited substantial presystemic metabolism (50%). The rat excreted a much higher percentage of radioactivity into the feces and formed an additional unidentified metabolite. The most comparable species with respect to humans metabolically was the mouse. The metabolism and excretion of K was similar following iv, po, and im doses within each species studied.

Single intravenous dose and steady-state oral dose pharmacokinetics of nicardipine in healthy subjects.

Nicardipine HCl oral doses (10-40 mg) were administered sequentially to six healthy subjects. For each regimen the capsule dose was administered every 8 hours (q 8 h) for 3 days and the plasma profiles of nicardipine and its pyridine analogue (M5) were determined following the last dose on day 4. Steady-state plasma concentrations of nicardipine for each subject were fitted very well by the Michaelis-Menten equation. An intravenous tracer dose (0.885 mg nicardipine HCl) was administered simultaneously with the final oral dose on the fourth day of the 30 mg q 8 h regimen. The steady-state bioavailability of nicardipine was shown to be dose-dependent and averaged 19 per cent (10 mg), 22 per cent (20 mg), 28 per cent (30 mg), and 38 per cent (40 mg). Nicardipine undergoes linear first-pass metabolism to M5. Other metabolic pathways are responsible for the saturable first-pass metabolism observed for nicardipine.

Bioequivalence of norethindrone and ethinyl estradiol for two different weight tablets with the same hormonal content.

Two tablets of differing weights, 100 mg (A) and 50 mg (B), of an oral contraceptive drug (OC) were compared with each other and to a solution (C) of the same components. The composition of the OC consisted of 1 mg of norethindrone (NET) and 0.035 mg of ethinyl estradiol (EE2). Both tablets were shown to differ from the solution, which was more rapidly absorbed, but were not significantly different from each other. Formulation means for NET and EE2, for each of the two products, were similar. Application of an interval test for the ratio of computed parameters demonstrated equivalence of the two formulations with respect to 0-24 hr area under the curve (AUC24) and total area under the curve (AUC+o+) for both NET and EE2 and with respect to concentration maximum (Cmax) for EE2. The data support the hypothesis for bioequivalence of the two formulations with respect to total absorption.

The metabolism and pharmacokinetics of nicardipine hydrochloride in man.

Studies have been carried out to investigate the disposition of nicardipine hydrochloride following intravenous and oral administration to male volunteers. Following oral administration of a radiolabelled dose, nicardipine was shown to be rapidly and extensively metabolised and to be rapidly eliminated from plasma. After intravenous infusion of nicardipine at 5 mg-1 for 3 h, plasma levels declined biexponentially, and clearance values were of the same order as hepatic blood flow. With repeated oral administration, 20 mg three times daily for 28 days, plasma levels rose over the first 3 days of administration and then declined to some extent. Possible reasons for this decline are discussed. Steady-state plasma levels and bioavailability show a nonlinear relationship with doses over the range 10-40 mg three times daily. Food consumption has been shown to reduce the bioavailability of nicardipine when the food is taken before or at the same time as nicardipine administration.

Pharmacokinetics of nicardipine following oral and intravenous administration in man.

The pharmacokinetics of nicardipine have been studied following oral and intravenous administration in man and the effects of food on nicardipine kinetics investigated. Following intravenous administration of nicardipine as an infusion plasma levels declined in a biphasic manner and plasma clearance values were of the same order as hepatic plasma flow. Following oral administration in the starved state nicardipine was rapidly absorbed but subject to presystemic elimination. Maximal plasma concentrations were achieved typically between 20 minutes and 2 hours after administration. The oral bioavailability of nicardipine determined by reference to a co-administered intravenous radiolabelled dose was found to be non-linearly related to dose. Bioavailability ranged from 15-45% approximately over the dose range 10-40 mg. Administration of nicardipine following a meal reduced the bioavailability of nicardipine.

Plasma levels and pharmacokinetics of norethindrone and ethinylestradiol administered in solution and as tablets to women.

Twenty-four normal adult female volunteers were dosed orally with a solution and tablet formulation containing the contraceptive combination of norethindrone (NET, 1.0 mg) and ethinylestradiol (EE2, 0.12 mg) in a crossover bioequivalence study. Blood was sampled sequentially following single oral doses and the plasma separated for analysis of NET and EE2 by specific radioimmunoassays. Comparisons of both drugs following a dose in solution and tablets were made with respect to the following parameters: (a) plasma concentrations at each sample time; (b) maximum plasma concentration (Cpmax); (c) time to maximum plasma concentration (Tmax); (d) total area under the plasma concentration vs. time curve (AUC), and (e) plasma half-life (t1/2). It was found that the tablet and solution doses were bioequivalent with respect to EE2 absorption. However, absorption of NET from solution and tablet doses exhibited significant differences with respect to plasma levels at certain time points as well as AUC (which were higher following the tablet dose), but Cpmax, Tmax and t1/2 were not significantly different. Pharmacokinetic analysis of both drugs following the tablet dose was carried out using a two-compartment open model. The absorption rate constant (ka) and peripheral to central compartment transfer rate constant (k21) were similar for NET and EE2, but statistically significant differences were observed with respect to the distribution rate constant (alpha), the central to peripheral transfer rate constant (k12), the overall elimination rate constant (ke1), and volume of distribution (V1/F). The elimination rate constant (beta) for both drugs showed a difference of borderline statistical significance.

Effect of Mylanta on naproxen bioavailability.

The effect of Mylanta on naproxen bioavailability was studied in 11 healthy volunteers. In separate experiments, single oral doses of naproxen (250 mg) and multiple oral doses (250 mg twice daily for 7 days) were administered with and without Mylanta. Coadministration of naproxen with Mylanta in the single-dose experiment did not significantly affect the area under the curve (579 vs. 580 microgram/ml X hr with and without Mylanta, respectively), time to peak serum concentration (2.5 vs. 2.6 hr), peak serum concentration (37.2 vs. 34.8 microgram/ml) or plasma half-life (16.1 vs. 16.4 hr). There was no significant difference between trough level naproxen concentrations at steady state (29.6 microgram/ml with Mylanta vs. 30.7 microgram/ml without Mylanta). The data were also used to investigate naproxen pharmacokinetics predicted by two different pharmacokinetic models, one of which allowed for protein binding. The nonlinear protein-binding model accurately predicted steady-state concentration, while the values predicted by the linear model exceeded actual values by 33-54%.

Relationship among particle size distribution, dissolution profile, plasma values, and anthelmintic efficacy of oxfendazole.

Three mean particle sizes of oxfendazole raw material (1.65 micron, lot A; 3.2 micron, 10t B; 12.0 micron, lot C) were prepared and identically formulated as corresponding (A, B, and C) suspensions at 2.26% (W/V) concentration. Studies involving microscopic examination, scanning electron microscope analysis, particle size distribution, and surface area measurement were carried out on raw materials. In vitro dissolution profiles were obtained for the suspensions. A comparative bioavailability study of these 3 suspensions was performed in 12 sheep with each sheep given each formulation in a Latin square crossover study design; oxfendazole was dosed at rate of 5 mg/kg of body weight. Plasma-value measurements were made followed by an analysis of various bioavailability studies. Plasma area values indicated that suspension C (dw = 12.0 micron) was significantly (P less than 0.05) less bioavailable than was suspension A (dw = 1.65 micron); there was no difference between suspension A and suspension B. Significant differences were not seen in biological half-life and maximum plasma concentrations. The term dw refers to that particle diameter (determined by Coulter counting) at which 50% of the oxfendazole mass was in the form of particles having a lesser diameter and 50% was in the form of particles having a greater diameter. In a separate study involving 20 Merino weaner sheep infected with benzimidazole-resistant Haemonchus contortus larvae, oxfendazole's anthelmintic efficacy was demonstrated in the 2.26% suspension dosage form (90% particles less than 10 micron) at a dosing rate of 5 mg/kg. A correlation was found between its anthelmintic activity and plasma area values when compared in individual sheep. Data demonstrated that substantial differences in particle size distribution of oxfendazole could influence its dissolution rate, plasma concentrations, and absorption characteristics, thus indicating that oxfendazole's absorption could be dissolution-rate limited.

Tiopinac absorption, distribution, excretion, and pharmacokinetics in man and animals.

[14C]Tiopinac disposition was evaluated in man, monkey, rabbit, mouse, minipig, and rat. The absorption of tiopinac was rapid and essentially complete in these species. Peak plasma levels occurred in less than 1 hr to 2 hr in all species. Following iv and po doses, tiopinac was recovered predominantly in the urine. In man, 93.2 and 2.6% of the administered radioactivity was recovered in the urine and feces, respectively. In the rat, 61.3% of the radioactivity was accounted for in urine and 32.7% in feces. In the mouse, radioactivity was concentrated in the kidney and liver, with tissue/plasma ratios ranging from 1.3 to 7.0 for kidney and 0.5 to 1.7 for liver. Radioactivity in all other tissues was generally lower than in plasma. Tiopinac was shown to be the major circulating entity in plasma, accounting for 90% of total radioactivity levels in the mouse and 61% in the rat. The half-life of tiopinac was 2.3 +/- 0.3 hr in man, 0.8 hr in the minipig, and 2.6 hr in the rabbit. The volume of distribution was 0.29 +/- 0.05 liter/kg in man, 0.16 liter/kg in the rabbit and minipig, and 0.42 liter/g in the mouse. Tiopinac was highly bound (99.5%) in human serum.