Pharmacokinetics and tolerability of oral rizatriptan in healthy male and female volunteers

AIMS: The pharmacokinetics and dose proportionality of rizatriptan single oral doses from 2.5 to 15 mg administered as solutions to healthy volunteers were studied. METHODS: In a randomized, crossover study with four periods, twenty-four healthy volunteers (12 males and 12 females) took single oral doses of 2.5, 5, 10, and 15 mg rizatriptan in Periods 1-4. In a fifth period, subjects received 4 mg intravenous (i.v.) rizatriptan as a reference. Plasma and urine rizatriptan concentrations were determined at several timepoints/intervals for 12 and 24 h, respectively. RESULTS: The arithmetic mean AUC values following single oral doses of 2.5, 5, 10, and 15-mg rizatriptan were 16, 33, 72, and 127 ng ml-1 h, respectively, in males; and 19, 42, 97, and 161 ng ml-1 h, respectively, in females. The overall bioavailability (F ) of rizatriptan was approximately 40% in males. Following the 4 mg reference i.v. dose, the apparent plasma clearance (CL) and renal clearance (CLr ) were 1042 and 225 ml min-1, respectively, in males; and 821 and 174 ml min-1, respectively, in females. CONCLUSIONS: The disposition kinetics of oral rizatriptan were linear for doses of 2. 5-10 mg in males, and for doses of 2.5-5 mg in females. However, the degree of nonlinearity for higher doses was minor for both genders. The plasma concentrations of rizatriptan were slightly greater in women compared to men but the difference was not considered to be clinically meaningful. Also, the clearance of rizatriptan appeared to be mainly nonrenal.     

Absorption, metabolism, and excretion of etoricoxib, a potent and selective cyclooxygenase-2 inhibitor, in healthy male volunteers.

[(14)C]Etoricoxib (100 microCi/dose) was administered to six healthy male subjects (i.v., 25 mg; p.o., 100 mg). Following the i.v. dose, the plasma clearance was 57 ml/min, and the harmonic mean half-life was 24.8 h. Etoricoxib accounted for the majority of the radioactivity (approximately 75%) present in plasma following both i.v. and p.o. doses. The oral dose, administered as a solution in polyethylene glycol-400, was well absorbed (absolute bioavailability of approximately 83%). Total recovery of radioactivity in the excreta was 90% (i.v.) and 80% (p.o.), with 70% (i.v.) and 60% (p.o.) excreted in urine and 20% in feces after either route of administration. Radiochromatographic analysis of the excreta revealed that etoricoxib was metabolized extensively, and only a minor fraction of the dose (<1%) was excreted unchanged. Radiochromatograms of urine and feces showed that the 6'-carboxylic acid derivative of etoricoxib was the major metabolite observed (> or =65% of the total radioactivity). 6'-Hydroxymethyl-etoricoxib and etoricoxib-1'-N-oxide, as well as the O-beta-D-glucuronide conjugate and the 1'-N-oxide derivative of 6'-hydroxymethyl-etoricoxib, were present in the excreta also (individually, < or =10% of the total radioactivity). In healthy male subjects, therefore, etoricoxib is well absorbed, is metabolized extensively via oxidation (6'-methyl oxidation >1'-N-oxidation), and the metabolites are excreted largely in the urine.     

Biopharmaceutics and metabolism of yohimbine in humans.

The biopharmaceutics of yohimbine (YO) and the pharmacokinetics of 10-hydroxy-yohimbine (10-OH-YO) and 11-hydroxy-yohimbine (11-OH-YO) were investigated in healthy subjects following i.v. (5 mg) and oral (8 mg) dosing. One subject was found as a slow hydroxylator of YO. The mean (+/-S.D.) oral absolute bioavailability of YO was 22.3+/-21. 5%. Total plasma clearance (CL) and renal clearance (CL(r)) of YO following i.v. dosing were 0.728+/-0.256 ml/min and 0.001+/-0.002 ml/min, respectively. Based on the steady-state volume of distribution (V(ss)), YO had a relatively low distribution (V(ss) = 32.2+/-12.1 l). The overall renal excretion of YO, 10-OH-YO and 11-OH-YO, expressed as percent of the dose of YO administered, were not different following i.v. and oral dosing, and were around 0.1, 0.2 and 14%, respectively. Following i.v. dosing of YO, the mean apparent terminal half-life of 11-OH-YO (347+/-63 min) was almost four times higher than that of YO (91.0+/-33.6 min) suggesting an elimination rate-limited kinetics for 11-OH-YO.     

Ranitidine: single dose pharmacokinetics and absolute bioavailability in man

1 Ranitidine single dose pharmacokinetics and absolute bioavailability have been studied in five healthy male volunteers. Following an overnight fast, 150 mg was given intravenously as a bolus injection or orally as a tablet formulation to each subject on separate occasions. 2 Following intravenous administration, plasma levels declined biexponentially. The mean (+/- s.d.) distribution half-life (t 1/2 alpha) was 6.6 +/- 1.6 min; plasma half-life (t 1/2 beta) was 1.7 +/- 0.2 h; the volume of distribution (V) was 96 +/- 9 1; total body clearance (CL) was 647 +/- 94 ml/min and renal clearance (CLR) 520 +/- 123 ml/min. 3 Following oral administration plasma levels showed a bimodal pattern with a first peak at 1.1 +/- 0.4 h and a second peak at 3 +/- 0 h. The absolute availability was 60 +/- 17%. The plasma half-life (t 1/2) of 2.3 +/- 0.4 h was significantly longer (P less than 0.05) after oral than after i.v. administration. 4 Renal excretion of unchanged ranitidine accounted for 79 +/- 9% of the dose after i.v. administration and for 27 +/- 7% after oral administration. 5 Our results suggest a more extensive biotransformation of ranitidine and biliary excretion of metabolites after oral administration while i.v. administration ranitidine is preferentially excreted unchanged in the urine.     

Pharmacokinetics and absolute bioavailability of sitafloxacin, a new fluoroquinolone antibiotic, in healthy male and female Caucasian subjects.

1. The aim was to compare the pharmacokinetics of sitafloxacin from a capsule formulation (dose of 500 mg sitafloxacin) and an intravenous (i.v.) formulation infused over 1 h (dose of 400 mg sitafloxacin) in healthy male and female subjects and to estimate the absolute bioavailability of sitafloxacin from the capsule formulation. 2. Following oral administration, sitafloxacin was rapidly absorbed, with a mean maximum concentration in plasma of 4.65 microgml(-1) occuring at median tmax = 1.25 h giving a mean AUC(0-infinity) = 28.1 microg h ml(-1). For the i.v. administration, a mean Cmax = 5.53 microm(-1) occurred at the end of the 1-h infusion with a mean AUC(0-infinity) = 25.4 microg h ml(-1). The mean terminal elimination half-life was 7.0 h (oral) and 6.6 h (i.v.). For the oral and i.v. formulations, the mean total plasma clearance was 296 and 263 mlmin(-1), respectively and the mean volume of distribution was 180 and 150 litres, respectively. 3. Within 48 h post-dose, approximately 61% (range 22-86%) of the administered dose was excreted unchanged in urine following capsule administration, compared with approximately 75% (range 42-101%) following the i.v. formulation. For both formulations, the renal clearance of sitafloxacin (means of 181 and 198 ml min(-1) for the capsule and i.v. doses, respectively) implies active tubular secretion of the drug. 4. The absolute bioavailability of sitafloxacin from the capsule formulation was high at 89%, with a 95% CI of 84-94%. The intersubject variability (CV%) in the sitafloxacin AUC(0-infinity) for the capsule was low at 18.6%. 5. Gender differences in the pharmacokinetics of sitafloxacin were small and would not warrant dose adjustment. 6. The findings show that the capsule formulation offers good oral bioavailability and merits further clinical evaluation of sitafloxacin as an orally effective fluoroquinolone antibacterial.     

Pharmacokinetics and excretion of phenol red in the channel catfish.

1. Disposition of phenol red was examined in channel catfish (Ictalurus punctatus) after oral or intravascular (i.v.) dosing at 10 mg/kg body weight. 2. Phenol red was not detectable in plasma, urine, or bile after oral administration. 3. After i.v. dosing, plasma concentrations of phenol red were best described by a two-compartment pharmacokinetic model with distribution and elimination half-lives of 2.3 and 21 min, respectively. The apparent volume of distribution at steady state (Vss) was 225 ml/kg and total body clearance (Clb) was 658 ml/h per kg. Plasma protein binding was 19%. 4. Biliary excretion was the primary route of elimination of phenol red; in 24 h, 55% of the i.v. dose was excreted in bile compared with 24% in urine. No metabolites were detected in these fluids. 5. The use of anaesthesia during dosing had no effect on the quantitative excretion of phenol red by renal or biliary routes.     

Pharmacokinetics of trimethylamine in rats,including the effects of a synthetic diet

1. The pharmacokinetic profile of trimethylamine (TMA) was examined in the male Wistar rat and the effects of a synthetic diet on TMA pharmacokinetics were also evaluated. 2. The concentrations of TMA and its N -oxide in blood were analysed by a sensitive headspace gas chromatographic assay. 3. The pharmacokinetics of TMA were essentially linear for intravenous (i.v.) bolus doses of 10-40?mg kg -1. Over the range of administered i.v. doses, the concentrations of TMA in blood declined approximately monoexponentially with half-lives of 2.03-2.48?h. The V d of TMA ranged from 3.2 to 4.39?l kg -1 and clearance ranged from 18.78 to 23.92ml?min -1 kg -1. The peak concentration of TMA in blood occurred at 1?h after oral administration of a 20?mg kg -1 dose and the bioavailability for the oral dose averaged 81%. 4. Peak concentrations of trimethylamine N -oxide (TMAO) in blood were attained at 0.75 and 1?h after i.v and oral administration of TMA (20mg kg -1), respectively. 5. Feeding the male Wistar rat with a synthetic diet resulted in a twofold decrease in the clearance of TMA. Furthermore, the concentration of TMAO in blood after i.v. administration of TMA peaked at 1.25?h in rat placed on the synthetic diet as opposed to 0.75?h in rat placed on normal laboratory rat chow. The altered pharmacokinetic profile of TMA and its N -oxide suggest a diminished drug-elimination capacity in rat placed on the synthetic diet. 6. Dietary modulation of flavin-containing monooxygenase (FMO) activity may explain the effects of diet on the pharmacokinetics of TMA and its N -oxide.     

Benzylacyclouridine. Pharmacokinetics, metabolism and biochemical effects in mice

The pharmacokinetics, tissue distribution and urinary excretion of the uridine (Urd) phosphorylase (EC 2.4.2.3) inhibitor 5-benzylacyclouridine (BAU) were studied in C57BL/6 female mice by reverse-phase HPLC. The plasma clearance of BAU after i.v. administration followed first-order kinetics with a half-life of approximately 36 min. Other pharmacokinetic parameters such as volume of distribution (17 ml), clearance rate (0.3 ml/min) and the elimination rate constant (0.019 hr-1) were relatively constant over a dose range of 5 to 240 mg/kg when based on a first-order clearance model. Following oral administration, BAU was rapidly absorbed from the gut; peak plasma concentrations occurred within 30 min and were approximately 60% of equivalent i.v. doses. The distribution of BAU between plasma and most major organs was rapid and efficient, the exceptions being spleen and brain, which maintained only 40% and 10%, respectively, of the plasma BAU concentration. Approximately 41% of the injected dose of BAU was recovered intact in urine within 24 hr. Another 27% appeared as a more polar metabolite which, at a concentration of 50 microM, did not inhibit murine Urd phosphorylase. A near linear relationship was observed between the injected dose of BAU and its ability to increase the plasma concentration of Urd; i.v. injections of 30, 120 and 240 mg/kg increased plasma Urd 3-, 7- and 15-fold respectively. The utility of these data in the design of combination chemotherapy regimens containing BAU and related compounds is discussed.     

Pharmacokinetics and bioavailability of ciramadol,a new analgesic

Healthy male volunteers participated in two studies of the pharmacokinetics of ciramadol, an investigational analgesic. For the dose-proportionality study, subjects received single i.v. doses of 15, 30, or 60 mg of ciramadol on three separate occasions. Serum samples and urine were collected 48 hr after each dose. Overall mean kinetic values for ciramadol were: volume of distribution, 1.5 liters/kg; elimination half-life, 3.7 hr; total clearance, 4.9 ml/min/kg. Clearance did not change systematically with dose. Mean 48-hr urinary excretion was 40% of the dose as the intact drug, with another 24% excreted as ciramadol conjugates; these were dose-independent. For the bioavailability study, subjects received a 30-mg dose of ciramadol i.v., i.m., or orally on three separate occasions. The mean absolute systemic availability of the i.m. dose was 98%; the absolute availability of the oral dose was 82%. Peak serum concentration of 235 and 155 ng/ml were attained at 0.27 and 1.5 hr after the i.m. and oral doses, respectively.     

Dose-dependent pharmacokinetics of 1-(2-deoxy-beta-D- ribofuranosyl)-2,4-difluoro-5-iodobenzene: a potential mimic of 5-iodo-2'-deoxyuridine

The dose-range pharmacokinetics of l-(2-deoxy-beta-D-ribofuranosyl)-2,4-difluoro-5-iodobenzene (5-IDFPdR), a C-aryl nucleoside mimic of IUdR, were studied in male Sprague-Dawley rats following single intravenous (i.v.) and oral doses. After i.v. administration, the blood clearance decreased from approximately 32 ml/min/kg at a dose of 15 mg/kg, to approximately 19 ml/min/kg when dosed at 54 mg/kg, and the elimination half-life increased from 8.4 min to 21.5 min, for the respective doses. While the dose-normalized area under the concentration-time curve (AUCnorm) remained practically unchanged (0.132 kg min ml(-1)) upon increasing the i.v. dose from 5 to 15 mg/kg, it increased by about 44% ( approximately 0.19 kg min ml(-1)) when the i.v. dose was increased from 15 to 54 mg/kg. Similarly, there was a dose-dependent increase in AUCnorm with increasing oral doses: AUCnorm increased by 49% as the oral dose increased from 20 to 40 mg/kg, and further by 55% as the oral dose was increased from 40 mg/kg to 54 mg/kg. For the respective oral doses, the elimination half-life increased from 24.5 min to 176 min, while blood clearance was reduced from approximately 37 ml/min/kg to approximately 17 ml/min/kg. The urinary recoveries of unchanged 5-IDFPdR and its glucuronides (as percent of the dose) were somewhat increased at higher doses. This increase was more pronounced following the highest oral dose. The total biliary recovery of 5-IDFPdR (as percent of the dose) was, however, decreased with increasing doses. The overall kinetic profile of 5-IDFPdR based on these data is suggestive of dose-dependent pharmacokinetics. Decreased elimination of 5-IDFPdR with increasing dose, as supported by longer elimination half-lives at higher doses, is one likely mechanism contributing to the dose-dependent behaviour of this compound. Saturable non-renal metabolism might explain the reduced total body clearance of 5-IDFPdR at higher doses, despite the unchanged or increased urinary clearance.For drugs exhibiting nonlinear kinetics, the dosage regimens may need to be carefully designed to avoid potential unpredictable toxicity and/or lack of pharmacological response associated with the disproportional changes in steady state drug concentrations on changing dose. Manifestation in the rat of nonlinear kinetics at doses of 5-IDFPdR, which may be of therapeutic relevance, warrants extended dose-range evaluations of this compound in future preclinical and clinical studies, to establish safe and efficacious dosage regimens.     

Pharmacokinetics in man of a new antiarrhythmic drug,cibenzoline

The kinetics of cibenzoline (UP 339.01), a new antiarrhythmic drug, was studied after i.v. and oral administration to 5 healthy subjects. Cibenzoline levels in plasma and urine cibenzoline were measured by a GLC method. After i.v. administration, the total clearance was 826 ml . min-1. The fraction of cibenzoline excreted unchanged in the urine was 0.602 and it was correlated with the creatinine clearance. After i.v. and oral administration, the renal clearances were 499 ml . min-1 and 439 ml . min-1, and the half-lives were 4 h 01 min and 3 h 24 min, respectively. The differences were not significant. Availability by the oral route was 0.92, the maximum plasma concentration being observed at 1 h 36 min. The results were compared with those for other antiarrhythmic drugs.     

Pharmacokinetics of the antidepressant levoprotiline after intravenous and peroral administration in healthy volunteers.

To investigate the pharmacokinetics and the disposition of levoprotiline after i.v. and p.o. administration and to assess the absolute bioavailability, 12 healthy volunteers (11 women, 1 man) were given a 10 min i.v. infusion of 15 mg and a p.o. dose of 75 mg in a two-way crossover study. Blood and urine samples were collected after each dose. Unchanged levoprotiline and the sum of unchanged and glucuronidated levoprotiline (= total levoprotiline) were determined by a specific gas chromatographic-mass spectro-metric method. Intravenous levoprotiline was rapidly and extensively distributed into extravascular sites of the body; the steady-state volume of distribution was 18.81 kg-1. The elimination of levoprotiline from blood was independent of the dosing route, the half-life being 18.8 h. Only 1.8 and 0.6 per cent of the i.v. and p.o. dose, respectively, were excreted unchanged in the urine, whereas 57 per cent of each dose were renally excreted as total levoprotiline. The absolute bioavailability of p.o. levoprotiline was 40 per cent. About 60 per cent of the dose was subject to a first-pass effect in the liver. The systemic blood clearance of levoprotiline, determined after i.v. dosing, was 885 ml min-1, the renal blood clearance after i.v. and p.o. dosing was only 16.0 and 14.2 ml min-1, respectively. Presystemic and systemic clearance of levoprotiline occurred predominantly by direct glucuronidation.     

The absorption, distribution, metabolism and excretion of rofecoxib, a potent and selective cyclooxygenase-2 inhibitor, in rats and dogs.

Absorption, distribution, metabolism, and excretion studies were conducted in rats and dogs with rofecoxib (VIOXX, MK-0966), a potent and highly selective inhibitor of cyclooxygenase-2 (COX-2). In rats, the nonexponential decay during the terminal phase (4- to 10-h time interval) of rofecoxib plasma concentration versus time curves after i.v. or oral administration of [(14)C]rofecoxib precluded accurate determinations of half-life, AUC(0-infinity) (area under the plasma concentration versus time curve extrapolated to infinity), and hence, bioavailability. After i.v. administration of [(14)C]rofecoxib to dogs, plasma clearance, volume of distribution at steady state, and elimination half-life values of rofecoxib were 3.6 ml/min/kg, 1.0 l/kg, and 2.6 h, respectively. Oral absorption (5 mg/kg) was rapid in both species with C(max) occurring by 0.5 h (rats) and 1.5 h (dogs). Bioavailability in dogs was 26%. Systemic exposure increased with increasing dosage in rats and dogs after i.v. (1, 2, and 4 mg/kg), or oral (2, 5, and 10 mg/kg) administration, except in rats where no additional increase was observed between the 5 and 10 mg/kg doses. Radioactivity distributed rapidly to tissues, with the highest concentrations of the i.v. dose observed in most tissues by 5 min and by 30 min in liver, skin, fat, prostate, and bladder. Excretion occurred primarily by the biliary route in rats and dogs, except after i.v. administration of [(14)C]rofecoxib to dogs, where excretion was divided between biliary and renal routes. Metabolism of rofecoxib was extensive. 5-Hydroxyrofecoxib-O-beta-D-glucuronide was the major metabolite excreted by rats in urine and bile. 5-Hydroxyrofecoxib, rofecoxib-3',4'-dihydrodiol, and 4'-hydroxyrofecoxib sulfate were less abundant, whereas cis- and trans-3,4-dihydro-rofecoxib were minor. Major metabolites in dog were 5-hydroxyrofecoxib-O-beta-D-glucuronide (urine), trans-3, 4-dihydro-rofecoxib (urine), and 5-hydroxyrofecoxib (bile).     

Absorption and Disposition of a Selective Aldosterone Receptor Antagonist,Eplerenone, in the Dog

Purpose. The present study was conducted to characterize the pharmacokinetics of eplerenone (EP), a selective aldosterone receptor antagonist, and its open lactone ring form in the dog. Methods. Pharmacokinetic studies of EP were conducted in dogs following i.v., oral, and rectal dosing (15 mg/kg) and following intragastric, intraduodenal, intrajejunal, and intracolonic dosing (7.5 mg/kg). Results. After oral administration, the systemic availability of EP was 79.2%. Systemic availabilities following administration via other routes were similar to that following oral administration. The half-life and plasma clearance of EP were 2.21 hr and 0.329 l/kg/hr, respectively. Plasma concentrations of the open lactone ring form were lower than EP concentrations regardless of the route of administration. The C-14 AUC in red blood cells was approximately 64% and 68% of the plasma AUC for i.v. and oral doses. Percentages of the dose excreted as total radioactivity in urine and feces were 54.2% and 40.6%, respectively, after i.v. administration, and 40.7% and 52.3%, respectively, after oral administration. The percentages of the dose excreted in urine and feces as EP were 13.7% and 2.5%, respectively, after i.v. administration, and 2.1% and 4.6% after oral administration, respectively. Approximately 11% and 15% of the doses were excreted as the open form following i.v. and oral doses. Conclusions. EP was rapidly and efficiently absorbed throughout the gastrointestinal tract, resulting in a good systemic availability. The drug did not preferentially accumulate in red blood cells. EP was extensively metabolized; however, first-pass metabolism after oral and rectal administration was minimal. EP and its metabolites appear to be highly excreted in the bile.     

Pharmacokinetic evaluation of (-)-6-aminocarbovir as a prodrug for (-)-carbovir in rats.

The recently synthesized carbocyclic 2',3'-didehydro-2',3'-dideoxy-6-deoxy-6-amino-guanosine [(-)6AC] was evaluated as a prodrug for carbovir, carbocyclic 2',3'-didehydro-2',3'-dideoxyguanosine [(-)CBV] in seven male Sprague-Dawley rats. A randomized three-way cross-over design was used. Rats were assigned to receive the following treatments: a 20 mg/kg (-)6AC infusion, 40 mg/kg (-)6AC orally, and a 20 mg/kg (-)CBV infusion. Blood samples were collected over 480 min, and urine was collected for up to 48 hr. A 2- to 3-day washout period was observed between treatments. Following i.v. infusion, (-)6AC concentrations in the blood declined rapidly in a monoexponential pattern with an elimination half-life of 11.3 +/- 3.3 min (mean +/- SD, n = 7). The time-averaged total body clearance was 115.7 +/- 32.6 ml/min/kg. The fraction of the dose excreted unchanged in urine was 0.28 +/- 0.06. The fraction of the (-)6AC dose metabolized to (-)CBV was 0.48 +/- 0.14. Following oral administration of (-)6AC, the bioavailability of (-)CBV was 46.2 +/- 9.9% (n = 6) in comparison with the bioavailability of approximately 20% previously obtained after an oral dose of (-)CBV. The Cmax of (-)CBV after a 40 mg/kg oral dose of (-)6AC was 1.65 +/- 0.7 micrograms/ml as compared with the previously reported Cmax of 1.00 microgram/ml obtained after a 60 mg/kg oral dose of (-)CBV. (-)6AC has considerable potential for the improvement of the extent of absorption of (-)CBV from oral dosing.     

Comparative study of the absolute bioavailability of four oral digoxin preparations (author's transl)

In a randomized cross over study on 19 normal subjects the absolute bioavailability of four oral digoxin preparations (Digacin containing a silica gel matrix as preparation A and three other commercial digoxin tablet preparations, B, C and D) were investigated applying digoxin in a daily dose of 0.25 mg for 10 consecutive days. On day 8, 9 and 10, the serum digoxin concentration and the amount of digoxin excreted with 24-h urine were measured radioimmunologically. After i.v. administration the mean serum digoxin concentration amounted to 0.58 ng/ml. With oral administration preparation A achieved the highest concentration (0.51 ng/ml) and preparation C the lowest (0.42 ng/ml). Accordingly, after i.v. administration 118 microgram digoxin were excreted with the 24-h urine and 95 microgram after the oral preparation A and 73 microgram after preparation C, respectively. From the serum concentrations and the amount excreted with the urine the absolute bioavailability was calculated: 88.0 and 80.4%, respectively, for preparation A, 82.5 and 67.2% for preparation B, 72.7 and 61.8% for preparation C, 76.2 and 67.3% for preparation D.     

Pharmacokinetic profile of a modified release formulation of trimetazidine (TMZ MR 35 mg) in the elderly and patients with renal failure

Objectives - To study the effect of age and renal function on the pharmacokinetic profile of a modified release tablet of trimetazidine (TMZ MR 35 mg) administered twice daily.Methods- Study 1: Twelve healthy elderly subjects (CL(creat) 72+/-8 ml/min, 72+/-4 years mean+/-SD) and eight young volunteers (CL(creat) 134+/-18 ml/min, 25+/-8 years) received TMZ MR 35 mg b.i.d. (eight doses). Study 2: eight patients with severe renal failure (CL(creat.) 17+/-5 ml/min, 54+/-10 years), five patients with moderate renal failure (CL(creat.) 39+/-6 ml/min, 54+/-15 years) and eight volunteers (CL(creat.) 104+/-17 ml/min, 53+/-9 years) received TMZ MR 35 mg b.i.d. (patients: ten doses, volunteers: eight doses). Serial blood and urine samples were obtained following administration of the last dose in each study. TMZ plasma and urine concentrations were determined by gas chromatography (NPD-detector). The resulting data were analysed using standard non-compartmental pharmacokinetic methods.Results- Study 1: Elimination half-life of TMZ was significantly longer and renal clearance significantly lower in the elderly subjects. Study 2: In patients with either moderate or severe renal failure, exposure (AUC(0-24)) was significantly increased and renal clearance (CL(R)) was significantly decreased. Significant correlations were observed between CL(creat) and CL(R) (r=0.94) and between CL(creat) and AUC(0-24) (r=-0.94).Conclusion - With repeated administration of TMZ MR 35 mg b.i.d., a decrease in CL(creat) is directly related to a decrease in CL(R) and results in an increase in exposure to TMZ.     

Dependence of the renal excretion of theophylline on its plasma concentrations and urine flow rate in asthmatic children

The dependence of the renal excretion of theophylline on its plasma concentration and urine flow rate has been investigated in asthmatic children of either sex. One group (age 12.25 +/- 0.80, mean +/- s.d. n = 8) was given aminophylline intravenously (i.v.), while another (age 10.00 +/- 3.64 n = 14) was given a sustained release preparation of theophylline orally (single dose and repeated doses). Unchanged drug (11.6% +/- 1.75) was excreted in the urine corresponding to a renal clearance of 10.6 +/- 1.6 mL h-1kg-1. Time dependence of the renal clearance of theophylline was found only after i.v. administration. Dependence of the renal clearance on urine flow rate was found both after i.v. administration and at steady state, but not after a single oral dose of theophylline. After oral administration, renal clearance of theophylline was higher at steady state than after a single dose (0.58 +/- 0.06 L h-1 kg-1 vs 0.23 +/- 0.03 L h-1 kg-1), while urine flow rate was lower (1.1 +/- 0.5 mL min-1 vs 1.8 +/- 0.9 mL min-1). High correlation of theophylline plasma concentration and theophylline excretion rate was obtained in 10 of 14 patients after administration of a single oral dose of the preparation (r = 0.8567 to 0.9830). There was no dose dependence of the renal clearance of the drug either after a single dose, or at steady state.     

Disposition and pharmacology of propofol glucuronide administered intravenously to animals.

1. Propofol glucuronide (PG) is the major human metabolite of the i.v. anaesthetic propofol, 2,6-diisopropylphenol. 2. Bolus i.v. doses of 14C-PG (1 mg/kg) to rat and dog were eliminated in urine (40 and 66% respectively) and faeces (48 and 19%); 25 and 48% of the dose were excreted unchanged in urine. 3. In dog, PG was distributed from plasma (t 1/2 4 min) into a volume equivalent to extracellular water and eliminated with t 1/2 80 min. Total body clearance was 1.8 ml/min per kg, and renal clearance about 20% GFR. In rat, plasma 14C concentrations were about one-tenth those in dog, thus PG levels were not quantified. 4. Propofol was not detected in the plasma showing that PG is hydrolytically stable. Enterohepatic circulation of PG occurred in rat and to a lesser extent in dog. Metabolites, mainly side-chain hydroxylation products, were evident in both species from 4 h after dosing. 5. Bolus i.v. doses of PG (200 mg/kg) showed no hypnotic activity in mice.     

Intravenous pharmacokinetics and metabolism of the reactive oxygen scavenger alpha-phenyl-N-tert-butyl nitrone (PBN) in the cynomolgus monkey

The pharmacokinetics and metabolism of the antioxidant and reactive oxygen scavenger alpha-phenyl-N-tert-butyl nitrone (PBN) was examined in the male cynomolgus monkey after intravenous administration. Following an i.v. bolus dose of 5 mg/kg, plasma concentrations of PBN declined in a bi-exponential fashion. PBN demonstrated a moderate plasma clearance (CL(p) = 27.02 +/- 6.46 ml/min/kg) and a moderate volume of distribution at steady state (Vd(ss) = 1.70 +/- 0.23 l/kg), resulting in a terminal elimination half-life of 0.76 +/- 0.25 h. The corresponding area under the curve (AUC(0-infinity)) was 3.20 +/- 0.77 microg-h/ml. Scale-up of the in vitro microsomal intrinsic clearance data for PBN afforded a blood clearance (CLb) value of 22 ml/min/kg, which was in reasonable agreement with the observed in vivo CLb. Monkey liver microsomes catalyzed the NADPH-dependent monohydroxylation of PBN to the corresponding alpha-4-hydroxyphenyl-N-tert-butylnitrone (4-HOPBN) metabolite. The formation of 4-HOPBN and its corresponding O-glucuronide was also discernible upon qualitative analysis of pooled (0-24 h) monkey plasma and urine samples. Less than 5% of the administered dose was excreted as unchanged PBN in the urine, suggesting that P450-catalyzed metabolism constituted the major route of PBN clearance in the primate. In conclusion, the pharmacokinetic attributes and the clearance mechanism of PBN in the cynomolgus monkey is similar to that observed in the Sprague-Dawley rat.