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.

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.

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.

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.

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.

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.

Biliary excretion of diethylstilbestrol in the rhesus monkey.

The biliary excretion of diethylstilbestrol in the bile fistula rhesus monkey was investigated during exogenous taurocholate- and taurodehydrocholate-induced choleresis. Following intravenous administration, 36% of the dose was excreted into the bile (as diethylstilbestrol monoglucuronide) and 53% in the urine (as diethylstilbestrol monoglucuronide plus more polar unidentified metabolites). During the steady-state infusion of diethylstilbestrol, with taurocholate-induced choleresis, a bile flow dependent transport for the biliary excretion of diethylstilbestrol monoglucuronide was observed. Evidence for carrier-mediated transport of this metabolite was a bile-to-blood concentration ratio which ranged from 228 to 279 during steady-state experiments. In vitro experiments indicated that diethylstilbestrol monoglucuronide forms an association with taurocholate, as well as the micellar structures of bile, resulting in a severalfold enhancement of solubility above that in aqueous buffer alone. Taurodehydrocholate, a non-micelle-forming bile salt, did not interact with this metabolite and had no effect on its solubility. Substitution of taurodehydrocholate for taurocholate during the steady-state infusion of diethylstilbestrol produced no significant changes in the transport of diethylstilbestrol monoglucuronide from blood to bile.

Cloprednol bioavailability in humans.

The bioavailability of cloprednol, a new systemic corticosteroid, was examined in a 12-subject crossover study in which two capsules, a tablet, and a solution were tested. Plasma was analyzed for cloprednol by a GLC-mass spectrometric method. The biological half-life, peak plasma concentration, peak time, plasma concentration at all sampling times, and plasma areas were evaluated for differences (p less than or equal to 0.05) in comparisons of pairs among the four formulations. An analysis of variance revealed that cloprednol was absorbed to the same extent from all formulations and rapidly cleared from the plasma with a half-life of 1.86 +/- 0.36 (SD) hr. All plasma profile parameters from the solid dose formulations were the same, demonstrating bioequivalence in both rate and extent of absorption. Significant differences were observed between the solution and solid dose formulations with respect to peak time, 15-min plasma concentration, and 0-30 min area, indicative of faster absorption from the solution; however, total plasma areas were the same for all four formulations. Comparison of plasma cloprednol levels in this study to those of a prior intravenous-oral dose study suggests that cloprednol was completely bioavailable from all formulations.