Acecainide pharmacokinetics in normal subjects of known acetylator phenotype.

The purpose of this study was to determine the pharmacokinetics of acecainide (formerly N-acetylprocainamide) in six normal subjects of known acetylator phenotype. Three subjects were fast acetylators and three slow acetylators by sulfapyridine phenotyping criteria. Each subject received a 20-min, 3 mg kg-1 intravenous acecainide infusion. Concentrations of acecainide, procainamide, and their deethylated metabolites were measured in serum and urine samples using HPLC. Acecainide renal clearance, nonrenal clearance, steady-state volume of distribution, and other pharmacokinetic parameters were estimated using standard approaches. Acecainide renal clearance and steady-state volume of distribution were (mean +/- SD) 13.6 +/- 1.581 h-1 and 135 +/- 20.31, respectively, and were not significantly different in fast and slow acetylators. Acecainide nonrenal clearance in the six subjects was 3.0 +/- 1.01 h-1; however, nonrenal clearance in slow acetylators was 1.8 times that in fast acetylators (3.9 vs 2.21 h-1, p = 0.012) with clear separation of the subjects into two groups when the data were grouped by acetylator phenotype. The nonrenal clearance of acecainide was inversely correlated with percentage sulfapyridine acetylation. Computer simulations were conducted to explore possible explanations for the observed difference in nonrenal clearance.     

Pharmacokinetics of isosorbide dinitrate after intravenous infusion in human subjects

Plasma concentrations of isosorbide dinitrate have been measured after intravenous infusion of drug at a rate of 5·0 mg h^?1 for 150 min and after single equal oral doses of 12·5 mg of drug in solution to two normal human subjects. During the infusion, uneven plateau concentrations were approached after 30 min. The calculated average steady-state plasma levels were 258 ng ml^?1 and 514 ng ml^?1 in the two subjects respectively. The half-life of elimination of isosorbide dinitrate after termination of the infusion was 9–10 min. After oral doses, peak plasma levels of 26·6 ng ml^?1 and 12·7 ng ml^?1 occurred at 10 min and 20 min in the two subjects respectively. The terminal half-life of drug after the oral doses was much longer than the elimination half-life (about 10 min), and was associated with the absorption phase. Fairly good agreement was obtained between the observed concentrations and those predicted by a one-compartment open model. The systemic availability of isosorbide dinitrate after the oral doses was up to only 3 per cent of the equal doses infused, indicating that presystemic elimination processes accounted for very large proportions of the oral doses. The systemic clearances of drug after infusion of 0·32 1 min^?1 and 0·161 min^?1 were unexpectedly low for a drug of reported high liver extraction ratio.     

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.     

Pharmacokinetics of fluvoxamine maleate after increasing single oral doses in healthy subjects

The pharmacokinetics of fluvoxamine after single oral administration of 25, 50, and 100 mg fluvoxamine maleate was studied in a three-way cross-over study in 12 healthy male subjects. Fluvoxamine was administered orally in a solution. For doseproportionality, AUC, and C_max-dose relationships were evaluated by linear regression. Plasma concentrations increased in a linear dose-dependent manner in the dose range between 25 and 100 mg; t_1/2 and T_max showed no significant differences among treatments. Fluvoxamine was well tolerated.     

Studies on the mutagenic activity of hydralazine and dihydralazine in Salmonella typhimurium strains differing in expression of antioxidant genes

The mutagenic activity of two antihypertensive drugs, hydralazine and dihydralazine was investigated in oxyR-proficient (TA104) and -deficient (TA4125) Salmonella typhimurium strains showing different ability to induce proteins involved in protection of the cells against oxidative damage. The results of the Ames test demonstrated that dihydralazine, in contrast to hydralazine, was mutagenic for oxyR⁻ strain at concentrations that were nonmutagenic for oxyR⁺ strain. The scavenger of superoxide anion, superoxide dismutase decreased in both strains the number of revertants induced by dihydralazine but not by hydralazine. The results may suggest that active oxygen species generated by dihydralazine contribute to its mutagenicity.     

Pharmacokinetics of benzydamine after intravenous, oral, and topical doses to human subjects

The pharmacokinetics of the anti-inflammatory drug benzydamine were determined after intravenous infusion of 5 mg to six healthy male subjects. Benzydamine was characterized as a drug of relatively low systemic clearance (ca. 160 ml min-1) but high volume of distribution (ca. 1101); the apparent terminal half-life in plasma was ca. 8 h. Benzydamine was well absorbed after oral administration, as indicated by a mean systemic availability of 87 per cent. However, absorption of the drug was low (less than 10 per cent of the dose) after its use by male subjects as a mouthwash, or after its application to female subjects as dermal cream and vaginal douche preparations. The data suggest that benzydamine is generally not well absorbed through the skin and non-specialized mucosae, thereby limiting unrequired systemic exposure to this drug when it is used by these routes.     

Plasma concentrations of disulfiram after injection of suspended micropellets into alcoholic subjects.

The disposition of disulfiram after administration in a new formulation was studied in rats and alcoholic patients. The suspension consisted of microcrystals suspended in a mixture of propylene glycol and water and injected subcutaneously into rats and humans; the course of the plasma concentration of diethyldithiocarbamate with time was followed by gas-liquid chromatography. Systemic delivery of disulfiram was observed to occur for a month. The data demonstrate that this form has the properties of a sustained-release formulation when implanted subcutaneously. There was no evidence of local or systemic adverse reactions.     

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.     

Clinical pharmacokinetics of procaterol: dose proportionality after administration of single oral doses.

Procaterol is a potent, orally active beta 2-agonist bronchodilator useful in the treatment of reversible bronchospastic disease. It is effective when administered as single or multiple (Q8H) 50 and 75 micrograms doses. As part of the clinical development of procaterol, the pharmacokinetics and dose proportionality of single 25, 50, 75, and 100 micrograms doses were investigated in 14 healthy subjects. Serial blood samples were collected for 16 h and urine was quantitatively collected for 48 h following administration of each dose. Procaterol concentrations in plasma and urine were determined using sensitive and specific radioimmunoassay methods. Mean values for tmax, the apparent elimination rate constant, Cl/F, renal clearance, and per cent of dose excreted unchanged in urine were similar for all doses. Dose-normalized AUC, Cmax, and amount excreted unchanged in urine (Ae) were also similar across dosage levels. Thus, the pharmacokinetics of procaterol appear to be proportional to dose over the range of doses studied.     

Adverse effects of single therapeutic doses of diazepam on performance in normal geriatric subjects: Relationship to plasma concentrations

Elderly normal volunteers (N=12, mean age 70.4 years) were administered placebo or diazepam 2.5, 5, 10 mg in four consecutive sessions separated by at least a 1-week interval. Memory and psychomotor performance and plasma diazepam concentrations were assessed at baseline and at 1 and 3 h following drug administration. Significant impairments were found in response to all doses of diazepam. The maximum impairment occurred at 1 h, which coincided with the highest plasma concentration of the drug.     

Phenylpropanolamine pharmacokinetics in dogs after intravenous, oral, and oral controlled-release doses

An adaption of a published high performance liquid chromatographic (HPLC) assay for phenylpropanolamine (PPA) in plasma was used to examine PPA pharmacokinetics in dogs. Plasma was extracted into ethyl acetate after the addition of 3.5 per cent sodium carbonate, and was then back-extracted into aqueous acetic acid. The acetic acid was injected onto a cyano column using a mobile phase of acetonitrile, dilute hydrochloric acid, and sodium heptane sulfonate. Detection was by UV absorbance at 210 nm. The relative standard deviation of replicate assays averaged 5.2 per cent over a concentration range of 50-1750 ng ml-1 plasma. PPA extraction recovery exceeded 90 per cent. The limit of detection was 30 ng ml-1 using 0.5 ml plasma and injecting 10 microliter. PPA disposition was characterized in three dogs administered PPA i.v. and orally in immediate-release and controlled-release formulations. The terminal elimination half-life averaged 3.5 +/- 0.5 h after the i.v. dose. Oral absorption from the immediate-release capsule was rapid and bioavailability was 98.2 +/- 6.9 per initial rapid cent. PPA absorption from the controlled-release dosage form was biphasic; an rapid phase was followed by a second, slower absorption phase which continued over 16 h. Plasma PPA concentrations then declined with a half-life roughly parallel to the i.v. and oral immediate-release half-lives. Oral bioavailability from the controlled release tablet was 93.7 +/- 5.9 per cent.     

Pharmacokinetics of furosemide after three different single oral doses

Furosemide solution was orally administered to 21 healthy adult males to determine dose proportionality over the dose range used and the reproducibility of disposition following a repeated dose. Furosemide solution was given in doses of 20, 40, and 80 mg, with the 40 mg dose repeated once. Blood was collected for 12 hours post-dose and urine for 24 hours. The maximum plasma concentrations resulting from 20, 40, and 80 mg doses were significantly different (p less than 0.05). Dose normalized maximum concentrations for the 20 and 80 mg doses were significantly different (p less than 0.05). Mean time to Cpmax was 50 minutes, with no differences observed among doses. Plasma AUCs were significantly different (p less than 0.05) for 20, 40, and 80 mg. Dose normalized AUCs were not significantly different. Mean amounts of furosemide in urine (Xu) were 9.62, 16.7, and 32.0 mg for the 20, 40, and 80 mg doses, respectively. These amounts were significantly different (p less than 0.05); dose normalized amounts were not significantly different. Renal clearances of furosemide following the three doses were not significantly different. Regressions of Cpmax, AUC and Xu on dose were significant. There were no significant differences in Cpmax, tmax, AUC or Xu for 40 mg given on two separate days. Renal clearance of furosemide was statistically different for 40 mg given on two separate days, but the difference was not clinically significant. The pharmacokinetics of furosemide are linear over the dosage range studied. Furosemide 40 mg given on two separate days results in similar disposition parameters.     

The pharmacokinetics of escitalopram after oral and intravenous administration of single and multiple doses to healthy subjects

The pharmacokinetics of escitalopram (S-citalopram) and its principal metabolite, S-demethylcitalopram (S-DCT), were investigated after intravenous and oral administration to healthy subjects. After intravenous infusion of escitalopram, the mean systemic clearance and volume of distribution were 31 L/h and 1,100 L, respectively. After oral administration of single or multiple doses, the absorption was relatively fast, with the maximum observed plasma or serum concentration (C(max)) attained after 3 to 4 hours. The mean half-lives were 27 and 33 hours, respectively; steady state was attained within 10 days. The area under the plasma or serum concentration time curve from time zero to 24 hours and C(max) was both linear and proportional to the dose. The apparent volume of distribution was around 20 L/kg. Comparison of the systemic and oral clearance implied a high absolute bioavailability. There was no evidence of interconversion from S-citalopram to R-citalopram either in plasma or in urine. Concurrent intake of food had no effect on the pharmacokinetics of escitalopram or its metabolite. All treatments were well tolerated.     

Plasma concentrations of perphenazine and its sulphoxide metabolite during continuous oral treatment

Plasma concentrations of perphenazine (PPZ) (Trilafon^®) and perphenazinesulphoxide (PPZSO) were estimated during a 2-week period in 16 patients receiving peroral PPZ treatment for various psychotic disorders. The results demonstrated that the average concentration of three plasma samples was a reasonably good expression of the steady-state plasma level despite a great fluctuation in the concentration from sample to sample. Increased doses in three of the patients resulted in disproportionate increases in the plasma levels. Neurological side effects were recorded and their relation to plasma concentrations are discussed.     

Plasma concentrations of megestrol acetate and medroxyprogesterone acetate after single oral administration to healthy subjects

Plasma concentrations of megestrol acetate (MA) were measured by radioimmunoassay (RIA) after a single oral dose of 60 mg either in the form of one tablet, or four 15 mg tablets, to 10 women 21-40 years old using a cross-over design. No statistically significant difference between the two preparations was observed with respect to plasma concentrations, the area under the curve from 0 to 24 h or the maximum concentration (c(max)). For comparison, data are presented on the plasma level of medroxyprogesterone acetate (MPA) following a single oral dose of 100 mg given using a cross-over design in two different tablet forms to 10 healthy men, when no significant difference was observed for these parameters. The mean c(max) for MA after 2.6 h was 43.9 ng/ml (range 21.7-87.7 ng/ml), whereas that for MPA at 3.1 h was 13.1 ng/ml (range 4.4-29.5 ng/ml) despite the higher dose. After 24 h immunoreactive MA and MPA ranged from 9.6 to 29.0 ng/ml and from 0.2 to 4.0 ng/ml respectively. Moreover, it was found that petroleum ether extraction gives the most specific result by RIA, although considerable amounts of metabolites are still co-estimated. By comparison with selected ion monitoring using GC-MS, metabolite interference in RIA increases with time after administration of the steroids and is considerably greater for MPA than for MA. It is concluded that after oral administration the relative bioavailability of MA is significantly better than that of MPA.     

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.     

Pharmacokinetic and pharmacodynamic studies of felodipine in healthy subjects after various single, oral and intravenous doses

The objective of this single-dose study was to evaluate the pharmacokinetics and haemodynamic changes in healthy male subjects following the administration of three oral (5, 15, and 40 mg) and two intravenous (1 and 3 mg) doses of felodipine, a new calcium antagonist with a selective effect on the peripheral resistance vessels. Felodipine was rapidly absorbed within 1 h when administered as an oral solution, but underwent extensive presystemic elimination. The systemic availability varied between 10 and 23 per cent. The disposition was adequately described by a two-compartment model: the disposition was essentially dose-independent up to 40 mg orally and 3 mg intravenously. Felodipine produced significant dose-dependent reduction of diastolic blood pressure and a significant reflexogenic increase in heart rate, without having any major effect on systolic blood pressure. These changes indicate that felodipine acts predominantly as an arteriodilator. The decrease in diastolic blood pressure and increase in heart rate were closely correlated with the plasma concentrations of unchanged felodipine, being maximal at 0.5 h and lasting for at least 4 h after the highest dose.     

Serum concentrations of methaqualone after repeated oral doses of a combination formulation to human subjects

Summary Concentrations of methaqualone have been measured in the serum of five male human subjects receiving five consecutive evening doses of a combination formulation containing methaqualone (250 mg), carbromal (300 mg) and benactyzine (0.33 mg) in each tablet. After administration of the first dose, mean peak serum concentrations of methaqualone (1.2 µg/ml) occurred at 3 h. After obtaining peak levels, mean concentrations of methaqualone declined rapidly during the next 6 h and there-after more slowly during the next 18 h. After administration of the last (fifth) dose, mean peak serum concentrations of methaqualone (1.9 µg/ml; 1.5 µg/ml above the predose level) occurred at 2 h. After attaining peak levels, mean concentrations of methaqualone declined rapidly during the next 6 h, and thereafter more slowly, with a half-life of approximately 10 h. Mean concentrations of methaqualone in serum samples 24 h after the second, third, fourth or fifth doses were not significantly different (0.3 µg/ml – 0.6 µg/ml) during this period of dosing. This suggests that significant accumulation of methaqualone in the serum did not occur during a period of five consecutive evening doses of the combination formulation.     

Plasma concentrations and relative bioavailability of naftidrofuryl from different salt forms

The relative bioavailability of the vasodilator naftidrofuryl from formulations containing its oxalate or citrate salt has been estimated using a specific HPLC assay, and a less specific fluorimetric assay, to measure plasma drug concentrations. The conclusions of the study were the same irrespective of the assay employed. The relative rate, but not the extent, of bioavailability of naftidrofuryl from the citrate salt (peak 1096 ng ml-1 at 0.76 h) was marginally greater (p = 0.003) than that from the oxalate salt (peak 922 ng ml-1 at 0.94 h). The degree of intersubject variability was similar after administration of either salt form. The mean half-life of naftidrofuryl was 1.8 h and its mean residence time was 2.5 h.     

Brain, plasma and tissue pharmacokinetics of risperidone and 9-hydroxyrisperidone after separate oral administration to rats

RATIONALE: Following an oral dose of risperidone (RSP), concentrations of its major metabolite 9-hydroxyrisperidone (9-OHRSP) were high in plasma and tissues but disproportionately lower in the brain compared to RSP, indicating that 9-OHRSP may have different pharmacokinetic properties. OBJECTIVES: To investigate non-compartmental pharmacokinetics of RSP and 9-OHRSP in plasma, brain and other tissues after separate administration of a single oral dose of 6 mg/kg RSP and 9-OHRSP to rats. METHODS: Plasma, brain, liver, lung, kidney and spleen tissues were collected at pre-dose and at 0.5, 1, 2, 5, 6, 12, 24, 36 and 48 h post-dose, homogenized in saline and assayed for RSP and 9-OHRSP using a sensitive and specific liquid chromatography tandem mass spectrometry method. RESULTS: The concentration-time curve of RSP and 9-OHRSP showed that they were readily absorbed and followed a multiphase elimination pattern. The terminal elimination half-life (t(1/2) ) of RSP after the RSP dose was longest in the liver (17.6 h) and shortest in the spleen (1.2 h). The t(1/2)of 9-OHRSP after the RSP dose was shorter in plasma (3.4 h) and other tissues (approximately 8-11 h) than that for RSP but it was longer in the spleen. However, the t(1/2) of 9-OHRSP after the 9-OHRSP dose was shorter in most tissues as compared to the t(1/2) of 9-OHRSP after the RSP dose. The area under the concentration-time curve (AUC) of RSP and 9-OHRSP was 6-67 times higher in the plasma and tissues than in the brain. AUCs of 9-OHRSP in tissues after the RSP dose were 2-5 times higher than those for RSP, except in the brain, where AUCs of RSP and 9-OHRSP were similar. CONCLUSION: Pharmacokinetics of 9-OHRSP in many tissues were different after RSP and 9-OHRSP doses. The reason for disproportionate brain levels of 9-OHRSP is not clear. The overall exposure to active drug in the brain as represented by AUC was similar after the RSP and 9-OHRSP doses and the 9-OHRSP is probably an equal contributor to the pharmacological actions of RSP.