Plasma tenoxicam concentrations after single and multiple oral doses

The pharmacokinetics of single- and multiple-dose administration of tenoxicam 20 mg were evaluated in 8 healthy males. Maximum plasma concentration (Cmax) after the first dose was 2.76 +/- 0.48 micrograms/ml (mean +/- s.d.) and the time to reach Cmax (Tmax) was 5.0 +/- 3.0 h. The area under the plasma concentration-time curve (AUC0-infinity) after a single administration of tenoxicam was 242.5 +/- 73.5 micrograms x h/ml. The elimination half-life (t1/2) was 66.3 +/- 15.8 h and the plasma concentration at 24 hours after dosing (Cmin) was 1.84 +/- 0.33 micrograms/ml. Steady-state plasma concentrations of tenoxicam were virtually reached after 10 consecutive daily doses. At steady-state, Cmax averaged 13.63 +/- 3.33 micrograms/ml and Tmax remained 5.0 +/- 3.0 hours. AUC within a dosing interval at steady-state was 262.2 +/- 67.0 micrograms x h/ml, Cminss was 9.67 +/- 3.25 micrograms/ml, and t1/2 averaged 74.2 +/- 13.3 h. The average fluctuation during multiple-dose administration was 26.8 +/- 8.0% and the accumulation ratio was 5.82 +/- 0.60. Steady-state pharmacokinetic parameters predicted from the first-dose data slightly underestimated observed values, but the results supported the assumption of linear pharmacokinetics during multiple-dose tenoxicam administration.     

Blood and plasma concentrations of butalbital following single oral doses in man

Blood and plasma concentrations of butalbital (from Fiorinal) were determined in a small group of healthy volunteers after single oral doses of 100 mg of butalbital. Butalbital was quantitated by high-performance liquid chromatography with ultraviolet detection. Typical blood concentrations of butalbital peaked at 2.1 mg/L and declined to 1.5 mg/L at 24 h. The half-lives in blood were between 35 and 87.5 h with a mean of 61 h. Whole blood to plasma ratios were also determined.     

Plasma codeine and morphine concentrations after a single oral dose of codeine phosphate

Plasma concentrations of codeine and its O-demethylated metabolite morphine were determined, by a sensitive and specific high performance liquid chromatography (HPLC) method, following a single oral dose of 60 mg codeine phosphate. Ten healthy volunteers received a single dose of 60 mg codeine phosphate. The plasma concentrations were analyzed for codeine and morphine at the 0.5, 1, 3, and 6 hours postdosing. The mean peak codeine plasma concentrations and tmax (time to reach maximum plasma codeine concentrations) were 88.1 ng/mL and 1.2 hours. Mean maximum concentrations of metabolically produced morphine was 2.7 +/- 0.6 ng/mL. The mean ratio of areas under the plasma concentration-time curves for morphine and codeine was 0.027. Thus, free morphine represented only about 2.7 +/- 1.8% of the free codeine area in each case.     

Potential cost-avoidance with oral extended-release morphine sulfate tablets versus morphine sulfate solution

The costs of acquiring, preparing, and administering morphine sulfate extended-release tablets and morphine sulfate solution were compared. Pharmacists at an acute-care community hospital timed the pharmacy and nursing components of the process of preparing and administering single doses of morphine sulfate extended-release tablets 60 mg and morphine sulfate solution 5 mg/mL. The labor cost of each step was determined by multiplying the mean time required to perform the task by the median of the wage scale for the person performing it. Acquisition costs and ancillary supply costs were determined, and the overall cost of each therapy was calculated. The total time required for providing single doses did not differ substantially. However, assuming a total daily morphine sulfate dosage of 120 mg, the time required for administering extended-release morphine sulfate tablets 60 mg twice daily was determined to be 8.90 minutes, compared with 23.44 minutes for solution (4 mL of 5-mg/mL solution) six times daily. Thus, although the cost of acquiring extended-release tablets was considerably higher than that of solution, the total daily cost of therapy with tablets was less than half that of therapy with solution. The potential for cost avoidance and the clinical advantages associated with extended-release morphine sulfate tablets make this formulation an attractive therapeutic alternative.     

Plasma concentrations and effects of methaqualone after single and multiple oral doses in man

Summary Three healthy subjects took methaqualone (1.0 mg/kg) once daily for 16 days. Equilibrium concentrations in plasma were established after multiple oral doses and there was a linear post-steady state decline in the log plasma concentration of methaqualone. The drug was also given as single oral doses and plasma concentrations were followed for 5 days (t_1/2=36 to 38 h.). Sedative effects were studied by psychophysiological tests and subjective ratings both in the single and multiple dose experiments. A significant impairment of flicker fusion discrimination ability occurred during the increase in the plasma concentration of the drug; maximum effects preceded peak plasma concentrations and the impairment disappeared whilst plasma concentrations were still high. The same effects were found in the subjective ratings. The drug was shown to have a possible tremorogenic effect after a hypnotic dose. One subject experienced sedation during the multiple dose experiment, despite the use of a low dose, an observation that should be taken into account, e.g. in car driving.     

Plasma concentrations and pharmacokinetics of dihydralazine after single oral doses to human subjects

After single oral doses of 20 mg of a suspension of dihydralazine sulphate to human subjects, the peak of mean plasma concentrations of dihydralazine of 47.0 ng ml-1 +/- 11.0 standard deviation (S.D.) (n = 7) was reached at 1 h. Mean concentrations declined biphasically with apparent half-lives of 0.57 and 4.96 h respectively. Dihydralazine was partly converted to hydralazine. The peak of mean plasma concentrations of the latter drug of 3.9 ng ml-1 +/- 1.7 S.D. (n = 7) occurred at 1-2 h after dosing with dihydralazine sulphate and declined to 1.5 ng ml-1 +/- 1.5 S.D. at 6 h. Of the seven subjects studied, three were classified as fast and four as slow acetylators. Mean clearances appeared to be slightly more rapid in fast acetylators (1.63 l min-1 +/- 0.32 S.D.) when compared to slow acetylators (1.31 l min-1 +/- 0.31 S.D.) but this difference and differences in plasma concentrations and in areas under the plasma drug concentration-time curves were not significant (p > 0.1).     

Pharmacokinetics of ketoprofen following single oral,intramuscular and rectal doses and after repeated oral administration

Summary The pharmacokinetics of ketoprofen was studied in the same healthy subjects after single oral, intramuscular and rectal doses, and after repeated oral administration. No significant difference in the mean t_1/2 (1.13–1.27 h) was observed after the different modes of administration. The mean [AUC] ₀ after rectal administration of a suppository showed the minimum significant difference (p<0.05) from that after oral administration of the capsule. The apparent volume of distribution (Vd/F) was approximately 10–15% of body weight. The renal contribution (mean, 0.10–0.15 ml/min/kg) to the plasma clearance of free ketoprofen was assumed to be, at most, 8.3–12.9%. The projected cumulative excretion of total (free plus conjugated) ketoprofen via urine exceeded 63–75% of the dose, of which approximately 90% was ketoprofen glucuronide. A mean of 71–96% and 73–93% of the oral capsule was estimated to be systemically available after administration of the intramuscular preparation and rectal suppository, respectively. In four of seven subjects, CPK concentration was elevated after the intramuscular injection. The mean steady-state concentration of ketoprofen in plasma ranged from 0.43 to 5.62 µg/ml after the final dose of a 50 mg q.i.d. regimen. The disposition data and plasma levels observed at steady-state were in agreement with those predicted from the single oral dose study. The accumulation ratio was 1.08±0.08. The results suggest that the rectal suppository can be recommended as an extravascular mode of administration of this drug.A preliminary account of this work was presented at the 10th Congress of Japanese Society of Clinical Pharmacology, Sapporo, 27 August 1979     

Biopharmaceutical evaluation of carprofen following single intravenous, oral, and rectal doses in dogs

Absorption and disposition characteristics of carprofen were compared in the dog after intravenous, oral, and rectal administrations. Rectal formulations included an aqueous solution and a suppository. Single doses of 100 mg carprofen were given in a cross-over design and plasma concentrations of unchanged drug were determined by HPLC. Plasma concentration-time profiles could be adequately described after intravenous and extravascular administrations by tri-and biexponential functions, respectively. After intravenous applications the basic disposition parameters could be determined: mean (+/- S.D.) elimination half-life was about 11.7 (+/- 3.1) h; volume of distribution ranged from 0.12 to 0.22 l kg-1 and total plasma clearance was about 0.017 +/- 0.003 l h kg-1. After oral dosing, carprofen was rapidly absorbed (time of maximum concentration: 0.83 +/- 0.61 h) and comparison with the intravenous solution indicated complete bioavailability. After rectal administration, the rate of absorption evaluated through tmax and calculation of mean absorption times was always slower than after oral dosing. Relative bioavailabilities of the drug from the suppository were about 20 per cent lower than from rectal solutions. No significant difference in rates of absorption of carprofen from rectal solution and suppository was seen; this allowed the conclusion that drug release from the semi-solid dosage form was not the rate-limiting step in carprofen absorption from the suppository. From the present study, it is concluded that rectal administration of carprofen offers an alternative to the oral route of drug intake.     

Pharmacokinetics and bioavailability of denaverine hydrochloride in healthy subjects following intravenous, oral and rectal single doses.

The neurotropic-musculotropic spasmolytic agent denaverine hydrochloride is used mainly in the treatment of smooth muscle spasms of the gastrointestinal and urogenital tract. Despite its commercial availability as a solution for intravenous or intramuscular administration (ampoule) and as a suppository formulation, no pharmacokinetic data in man was available to date. Therefore, the objectives of this clinical trial were to determine the basic pharmacokinetic parameters of denaverine after intravenous administration, to assess the feasibility of using the oral route of administration and to characterise the bioavailability of the suppository formulation. To achieve this, healthy subjects received 50 mg denaverine hydrochloride intravenously, orally and rectally in aqueous solutions and rectally as suppository in an open, randomised crossover design. Total body clearance, volume of distribution at steady-state and half-life of denaverine are 5.7 ml/min per kg, 7.1 l/kg and 33.8 h, respectively. The absolute bioavailability after oral administration of an aqueous solution is 37%. First-pass metabolism leading to the formation of N-monodemethyl denaverine was found to be one reason for the incomplete bioavailability after oral administration. Rectal administration of an aqueous solution of denaverine hydrochloride resulted in a decreased rate (median of C(max) ratios: 26%, difference in median t(max) values: 1.9 h) and extent (31%) of bioavailability compared to oral administration. Using the suppository formulation led to a further reduction in rate (median of C(max) ratios: 30%, difference in median t(max) values: 3 h) and extent (42%) of bioavailability compared to the rectal solution.     

Pharmacokinetics of azapropazone following single oral and intravenous doses

The pharmacokinetics of azapropazone (Prolixan) was studied in 7 healthy volunters following single oral and i.v. doses of 600 mg. After i.v. injection plasma concentration declined biexponentially with time. The half-life of the beta-phase was 13.6 +/- 2.6 h (mean +/- SD), the apparent volume of distribution 11.9 +/- 3.5 l, and the total clearance 10.1 +/- 2.1 ml . min-1. Following oral administration peak plasma concentrations occurred between 3 and 6 h and declined with a beta-phase half-life of 14.3 +/- 2.8 h. The binding of azapropazone to plasma proteins was high (ranging from 99.52 to 99.67% at a total plasma concentration of 75 micrograms/ml). The bioavailability of azapropazone when administered as capsules was 83 +/- 19%.     

Plasma kinetics of methaqualone in man after single oral doses

Summary Plasma concentrations of methaqualone were followed for several days after single oral doses in 5 healthy subjects. The analysis of methaqualone was performed by gas chromatography-mass spectrometry (mass fragmentography). The plasma levels of methaqualone were interpreted according to a two compartment model. The elimination rate of methaqualone was found to be much slower than has been reported previously, half lives in the -phase ranging from 19.6 to 41.5 h.     

Plasma mexiletine concentrations following combined oral and intramuscular administration

Summary Mexiletine in doses of 50, 100 and 400 mg was administered by intramuscular injection to a healthy subject and the resulting plasma concentrations were compared with those after 100 mg given intravenously. The bioavailability of mexiletine given by this route is complete and the kinetics are linear with dose. Plasma mexiletine concentrations resulting from 200 mg given orally with either two 4-ml intramuscular injections each containing 100 mg (Mexitil_® — for intravenous use) or one 2-ml intramuscular injection of an experimental preparation containing 200 mg were compared in 3 and 6 normal subjects respectively. Plasma levels within the therapeutic range of 0.75–2 µg/ml were attained at mean times of 28.7 and 42.5 min respectively. Apart from raised plasma creatine phosphokinase levels (as would be expected following an intramuscular injection) the tolerability of intramuscular mexiletine injections was satisfactory. Further studies in patients will be required to determine whether the combined oral and intramuscular administration of mexiletine is of value in acute myocardial infarction.     

Plasma concentrations and pharmacokinetics of idebenone and its metabolites following single and repeated doses in young patients with mitochondrial encephalomyopathy

Objective: The pharmacokinetics and tolerance of idebenone after single or repeated doses have been studied in young patients with mitochondrial encephalomyopathy. Results: No significant adverse effects were noted. In 3 out of 7 patients idebenone induced overall stimulation and improvement in arousal. Plasma concentrations of idebenone and its main metabolites were determined and the pharmacokinetic parameters of idebenone after single and repeated doses were estimated. During the single dose study, the mean plasma concentrations of idebenone and its main metabolites and mean pharmacokinetic parameters were comparable to published results (C_max = 452.2 ng ⋅ ml⁻¹, t_max = 2.3 h, AUC = 26 μg ⋅ ml⁻¹⋅ h, t_1/2β = 16.5 h). During the repeated doses study, no significant difference was found between mean residual plasma concentrations of idebenone on Day 2 (47 ng ⋅ ml⁻¹) and Day 5 (70.6 ng ⋅ ml⁻¹), and mean t_1/2β of idebenone after the single and after repeated dose studies, i.e., there was no evidence of accumulation. Although idebenone did not appear to accumulate during this study, the coadministration of anticonvulsants, often prescribed during mitochondrial encephalomyopathy, can affect its pharmacokinetics. Received: 2 January 1995/Accepted in revised form: 1 April 1996     

Self-rated sedation and plasma concentrations of desmethyldiazepam following single doses of clorazepate

Plasma concentrations of desmethyldiazepam (DMDZ) and intensity of self-rated sedation (SRS) were measured at multiple points in time during 6h after a single 15 mg oral dose of clorazepate dipotassium. Mean plasma DMDZ levels and mean SRS scores both became maximal at 1.0–2.5 h after drug dosage. By 6 h, however, mean SRS had returned to the predrug baseline score while mean DMDZ concentration fell only slighty from the maximum value. Disappearance of SRS despite persistence of high DMDZ levels might be due to adaptation or tolerance. If this is the case, subjective effects of benzodiazepines may depend upon duration of drug exposure as well as dose and concentration.     

Plasma and cerebrospinal fluid concentrations of temazepam following oral drug administration

Summary Thirteen male patients were administered 20 mg of temazepam orally 1 to 2 h prior to undergoing spinal anaesthesia for a urological procedure. Samples of blood and CSF were drawn just before insertion of the spinal and the concentration of drug estimated in these two media.The results obtained indicated that a highly significant correlation existed between the unbound concentration of temazepam in plasma and the concentration of drug present in CSF. Temazepam appeared to be an effective light pre-medicant in all of the subjects studied.     

Ampicillin concentrations in human oral tissues following a single oral administration of lenampicillin.

1. Ampicillin concentrations in serum (n = 20), gingiva (n = 12), jawbone (n = 13), dental follicle (n = 12), radicular granuloma (n = 2) and radicular cyst (n = 2) were measured in specimens obtained during 0.5-2.5 hr after a single oral administration of lenampicillin (equivalent to 500 mg of ampicillin). 2. Measurable ampicillin concentrations were found in all serum and tissues. 3. Ampicillin concentrations in serum and tissues except for some gingiva and jawbone exceeded MIC for 90% of clinically isolated strains of alpha-hemolytic Streptococci. 4. Ampicillin concentrations in gingiva and jawbone were below the MIC for 90% in 2 out of 12 and 4 out of 13 specimens, respectively.     

Ciprofloxacin concentrations in human fluids and tissues following a single oral dose

Ciprofloxacin is a new quinolone carboxylic acid derivative which exerts its antibacterial activity at very low concentrations against a wide spectrum of microorganisms. Ciprofloxacin serum and urine concentrations were studied in 10 healthy volunteers after a single 250 and 500 mg oral dose. The concentration in ascitic fluid was determined in four male patients undergoing paracentesis after a single oral 250 mg dose (two patients) and 500 mg dose (two other patients). The penetration of ciprofloxacin into the human tonsils and turbinate bones was also determined in eight patients undergoing tonsillectomy or turbinectomy 3 h after a single oral 250 mg administration. Ciprofloxacin concentrations were determined by an agar diffusion test utilizing E. coli as reference strain. Ciprofloxacin is rapidly absorbed after oral administration (Ka = 2.67 and 1.93 mcg/ml) and its serum concentration does not vary significantly with sex and dosage (Cmax = 2.61 and 1.99 mcg/ml after a single 500 mg and 250 mg oral dose). Urinary concentrations of ciprofloxacin are twice higher after a single 500 mg dose than after a 250 mg one and are still high after 24 h (37.2 and 25.3 mcg/ml). The concentrations of ciprofloxacin in ascites, tonsils and turbinate bones are several times higher than its MICs against the majority of Gram+ and Gram- aerobic bacteria. The in vitro activity of ciprofloxacin and its human pharmacology suggest a twice daily 250 of 500 mg dosing for infections caused by multiple antibiotic-resistant bacteria, and a once a day dose in the treatment of urinary tract infections.