Pharmacokinetics and pharmacodynamics of pentopril, a new angiotensin-converting-enzyme inhibitor in humans

In a single, ascending-dose tolerance study, nine healthy volunteers were given oral pentopril 50 to 750 mg (CGS 13945) in groups of three each. Disposition characteristics of pentopril and its active metabolite (CGS 13934) were determined using plasma concentration and urinary excretion data. The drug was absorbed rapidly following zero-order kinetics. The drug has an apparent volume of distribution of 0.83 L/kg and an oral clearance of about 0.79 L/hr/kg. Urinary excretions, calculated after 125- and 250-mg doses, showed a dose proportional urinary recovery of 21% (+/- 5%) for pentopril and 40% (+/- 5%) for CGS 13934. In the multiple-dose study of 125 mg orally q12h in six healthy subjects, the plasma concentrations for both drug and metabolite showed no appreciable accumulation of either compound, which was expected from their short pharmacokinetic half-lives (pentopril, less than 1 hr; CGS 13934, approximately 2 hr). In a separate pharmacodynamic study, drug and metabolite concentrations were evaluated against angiotensin-I (AI)-induced changes in blood pressure and plasma angiotensin-converting-enzyme (ACE) activity in healthy volunteers after single oral doses (range, 10-500 mg). The pharmacodynamic half-life for plasma ACE inhibition increased with the dose (10 mg, 1.5 hr; 500 mg, 9.8 hr). There was a close relationship between the plasma level of the metabolite and the inhibition of plasma ACE activity and AI-induced pressor response. A hyperbolic function adequately described the dependence of plasma ACE activity on plasma metabolite concentration with a concentration at half-maximal inhibition of 53 ng/mL.     

Oral, intraperitoneal and intravenous pharmacokinetics of deramciclane and its N-desmethyl metabolite in the rat

The pharmacokinetic properties of deramciclane fumarate (EGIS-3886), a new potential anxiolitic agent, and its N-desmethyl metabolite have been investigated in Wistar rats after 10 mgkg(-1) deramciclane fumarate was administered orally, intraperitoneally or intravenously. A highly sensitive, validated and optimized gas chromatographic method with nitrogen selective detection (GC-NPD) using a solid-phase extraction technique was used to determine plasma levels of the parent compound and its N-desmethyl metabolite. After oral administration the absorption of the parent compound was very fast (t(max) 0.5h). The maximum plasma concentration (C(max)) was detected at 44.9, > or =177.8 and > or =2643.0 ngmL(-1) after oral, intraperitoneal and intravenous administration of deramciclane, respectively. For the metabolite the respective Cmax values were 32.0, > or =25.4 and 51.0 ngmL(-1). The pharmacokinetic curves of both the parent compound and its metabolite showed enterohepatic recirculation for all administration routes. The biological half-life (tbeta 1/2) for deramciclane ranged from 3.42 to 5.44 h and for the N-desmethyl metabolite the range was 2.90-5.44 h, after administration of the drug by the three different routes. After intravenous administration AUC0-infinity, of deramciclane was 29.2- and 5.4-times higher than that observed after oral and intraperitoneal treatment, respectively. These AUC0-infinity ratios were only 2.1- and 1.5-times higher for the metabolite. The absolute bioavailability of deramciclane in rats was 3.42% after oral and 18.49% after intraperitoneal administration. The comparative pharmacokinetic study of deramciclane in rat after the different administration routes showed fast absorption. Furthermore, plasma levels were found to be administration route-dependent, low bioavailability of the parent compound indicated an extremely fast and strong first-pass metabolism. The apparent volume of distribution suggested strong tissue binding after administration of the drug by any of the three routes studied.     

Pharmacokinetics and metabolism of an alpha,beta-blocker, amosulalol hydrochloride, in mice: biliary excretion of carbamoyl glucuronide

The pharmacokinetics and metabolism of an alpha,beta-blocker, amosulalol hydrochloride, were investigated in mice. After intravenous administration (10 mg/kg), the plasma concentration of the unchanged drug declined biphasically, with a terminal half-life of 1.1 h. The maximum plasma concentrations were reached at 0.25 h after oral administration, and then declined with apparent half-lives of 0.8-1.3 h. The systemic bioavailability of a 10-mg/kg dose was 38.7%. The area under the plasma concentration curve increased more than proportionally to the dose, which suggests metabolic saturation. After oral and intravenous administrations of (14)C-labelled amosulalol hydrochloride, 64.7% and 81.0% of the radioactivity were recovered, respectively, in the urine within 48 h. HPLC-UV and LC/MS analyses demonstrated that the major urinary metabolite was the glucuronide of M-2 (desmethyl metabolite at the o-methoxyphenoxy group) followed by M-5, the M-3 glucuronide, and the M-4 glucuronide, in that order. In the bile sample, amosulalol carbamoyl glucuronide was found as a new metabolite of this drug.     

Simple and reliable radioreceptor assay for beta-adrenoceptor antagonists and active metabolites in native human plasma

Summary A radioreceptor assay (RRA) for the assay of beta-adrenoceptor antagonists in native human plasma is described. The hydrophilic antagonist³H-CGP 12177 was used as the radioligand. In contrast to the hydrophobic radioligand³H-dihydroalprenolol, which was investigated in parallel, the beta-adrenoceptor binding of³H-CGP 12177 by rat reticulocyte membranes was found not to be affected by inclusion of increasing proportions (0–66% of incubation volume) of human plasma in the assay. Thus, solvent extraction of drug and/or active metabolites was not necessary to avoid binding of the radioligand tracer to plasma added in the RRA. The assay of unprocessed samples was possible. Drug concentrations in plasma after oral administration of propranolol (240 mg) or carteolol (30 mg) to 6 healthy volunteers were measured by the RRA and in parallel by a chemical method. The results from both methods agreed when the plasma concentration kinetics of propranolol were investigated (elimination half-life: 3.9 h). In contrast, plasma concentrations of carteolol were consistently higher according to the RRA after oral administration of the drug. Identical concentrations, however, were found by the RRA and chemical method using plasma samples spiked with carteolol. Plasma concentrations of carteolol detected by the chemical method decline monoexponentially (elimination half-life: 5.4 h). A similar half-life of elimination for parent drug was found by the RRA (5.9 h), but an additional term describing the appearance of an active metabolite was necessary to account for the biphasic drug elimination (elimination half-life of metabolite: 17.3 h). The latter result is in agreement with the appearance of 8-hydroxy-carteolol as an active metabolite, which shows similar affinity for beta-adrenoceptors as the parent drug. The active metabolite, with a 3-fold longer elimination half-life than the parent drug, will prolong the duration of the clinical effects of orally administered carteolol. In conclusion, the RRA permits the determination of beta-adrenoceptor antagonistic activity in native human plasma at concentrations as low as 0.1-fold the IC₅₀-value of the drug or an active metabolite.     

The pharmacokinetics and bioavailability of a tracer dose of [3H]-mebendazole in man.

Five volunteers, whose ages ranged between 37 and 64 years, took part in a crossover study to determine the pharmacokinetics and bioavailability of mebendazole in man following intravenous and oral administration of a tracer dose of [3H]-mebendazole. Following intravenous administration, the average distribution half-life, elimination half-life and rate of clearance were 0.20 h, 1.12 h, and 1.063 min respectively. After oral administration of the solution, the average elimination half-life was 0.93 h, the apparent rate of clearance was 0.846 l/min, the average time to peak plasma concentration was 0.42 h, and the bioavailability of mebendazole was 22%. Comparison of metabolite area under the plasma concentration vs time data from each route of administration indicates that absorption of mebendazole from the gastrointestinal tract at this dose level is almost complete. The low bioavailability observed following oral administration at this dose level is postulated to be due to high first pass elimination. Approximately half of the administered dose of radioactivity following intravenous and oral administration was detected in the urine, and the major unconjugated metabolite of mebendazole was found to be 2-amino-5(6) [alpha-hydroxybenzyl]benzimidazole (IV), not 2-amino-5(6)benzoylbenzimidazole (II), as previously reported.     

Toxicokinetics of methyl paraoxon in the dog

The toxicokinetics of methyl paraoxon, the active metabolite of the organophosphorus insecticide methyl parathion, were studied in non-anaesthetized dogs after intravenous (2.5 mg/kg) and oral (15 mg/kg) administration of methyl paraoxon. After intravenous administration, distribution and elimination occured very rapidly and using the data from 5 min post-injection, the plasma concentration versus time curves could be fitted to a one-compartment open model. The mean half-life of elimination was 9.7 min, the average volume of distribution 1.76 l/kg and the average plasma clearance 126 ml/kg/min. After oral administration, peak plasma concentrations were obtained within 3–16 min, and the bioavailability varied from 5 to 71%. The hepatic extraction of methyl paraoxon measured in anaesthetized dogs, was high (70–92%). Comparison of the urinary excretion after intravenous and oral administration in two dogs indicated a gastrointestinal absorption of more than 60%. The kinetics of methyl paraoxon were linear in the dose range tested.     

Disposition of radiolabeled ifetroban in rats, dogs, monkeys, and humans.

Ifetroban is a potent and selective thromboxane receptor antagonist. This study was conducted to characterize the pharmacokinetics, absolute bioavailability, and disposition of ifetroban after i.v. and oral administrations of [14C]ifetroban or [3H]ifetroban in rats (3 mg/kg), dogs (1 mg/kg), monkeys (1 mg/kg), and humans (50 mg). The drug was rapidly absorbed after oral administration, with peak plasma concentrations occurring between 5 and 20 min across species. Plasma terminal elimination half-life was approximately 8 h in rats, approximately 20 h in dogs, approximately 27 h in monkeys, and approximately 22 h in humans. Based on the steady-state volume of distribution, the drug was extensively distributed in tissues. Absolute bioavailability was 25, 35, 23, and 48% in rats, dogs, monkeys, and humans, respectively. Renal excretion was a minor route of elimination in all species, with the majority of the dose being excreted into the feces. After a single oral dose, urinary excretion accounted for 3% of the administered dose in rats and dogs, 14% in monkeys, and 27% in humans, with the remainder excreted in the feces. Extensive biliary excretion was observed in rats with the hydroxylated metabolite at the C-14 position being the major metabolite observed in rat bile. Ifetroban was extensively metabolized after oral administration. Approximately 40 to 50% of the radioactivity in rat and dog plasma was accounted for by parent drug whereas, in humans, approximately 60% of the plasma radioactivity was accounted for by ifetroban acylglucuronide.     

Pharmacokinetics of nicorandil, a new coronary vasodilator, in dogs

The kinetic disposition of nicorandil, N-[2-( nitroxy )ethyl]-3- pyridinecarboxamide (1), and its main metabolic product, N-[2-(hydroxy)-ethyl]-3- pyridinecarboxamide (II), was studied after administering intravenous and oral doses (2.5 mg/kg) of nicorandil to the same beagle dogs. The plasma concentrations were measured using a high-performance liquid chromatographic method. The pharmacokinetic data derived from intravenous administration of nicorandil were: t1/2, 0.73 plus/minus 0.11 h; Vdarea , 0.67 plus/minus 0.04 L/kg; and total plasma clearance, 13.50 plus/minus 1.05 mL/min/kg. After oral administration, nicorandil was rapidly absorbed (tmax, 0.58 plus/minus 0.11 h). The oral bioavailability was calculated as 0.72 plus/minus 0.07. The metabolic formation of the corresponding alcohol after intravenous and oral administration of the parent compound appeared to occur quite efficiently, and its elimination half-life (3.09 plus/minus 0.25 and 3.69 plus/minus 0.88 h after intravenous and oral administration of nicorandil, respectively) was longer than that of the parent compound. Since the dose employed in this study was much higher than the expected therapeutic doses, whether such a good bioavailability after a lower dose of the drug would be obtained in humans remains unanswered.     

Serum concentrations and urinary excretion of pinacidil and its major metabolite, pinacidil pyridine-N-oxide following i.v. and oral administration in healthy volunteers.

Serum concentrations of pinacidil and its major metabolite pinacidil pyridine-N-oxide were determined following administration of both an intravenous solution and a sustained release oral preparation to healthy volunteers. Mean bioavailability of pinacidil was 57.1 +/- 13.7%. Following intravenous administration, the mean AUC0-8 h metabolite/AUC 0-8 h pinacidil ratio was 0.559 +/- 0.272 and after oral administration, 0.825 +/- 0.656. Only one subject had serum metabolite concentrations in excess of pinacidil during the intravenous study whereas three subjects achieved metabolite concentrations in excess of pinacidil during the oral study. The mean serum elimination half-life of metabolite was significantly longer than parent drug following intravenous administration (P less than 0.01) but not after oral administration. No significant difference was found in the maximum measured metabolite concentration (Cmax.m) between the studies. The time to Cmax.m was significantly delayed (P less than 0.001) following oral dosage. Twenty four hour urinary excretion of metabolite was significantly increased (P less than 0.001) following oral administration whilst that of pinacidil was decreased (P less than 0.02). These results suggest that pinacidil pyridine-N-oxide may be a 'first-pass' metabolite of pinacidil. In most patients pinacidil pyridine-N-oxide is unlikely to contribute significantly to the hypotensive effect of pinacidil.     

Pharmacokinetics of CS-866, a new angiotensin II receptor blocker, in healthy subjects

CS-866, a novel angiotensin II receptor blocker, is rapidly and completely metabolized to RNH-6270, its active metabolite. The pharmacokinetics of RNH-6270 following oral CS-866 or intravenous RNH-6270 administration was determined in 104 healthy male volunteers. The pharmacokinetics of RNH-6270 was linear over dose ranges of 1 to 32 mg (intravenous RNH-6270 administration) and 10 to 160 mg (oral CS-866 administration). The time to maximum plasma concentration of RNH-6270 after oral CS-866 administration ranged from 1.4 to 2.8 hours, and the terminal elimination half-life ranged from 12 to 18 hours. Absolute bioavailability of RNH-6270 after oral administration of CS-866 was 26%. Administration of CS-866 once daily for 10 days did not result in drug accumulation. When administered intravenously, RNH-6270 has a volume of distribution of 15 to 25 L. Approximately 35% to 50% of RNH-6270 is excreted unchanged in the urine. CS-866 was safe and well tolerated at doses of up to 160 mg/day.     

High-dose morphine and methadone in cancer patients. Clinical pharmacokinetic considerations of oral treatment

Several clinical studies have shown oral morphine and methadone to be effective in the treatment of intractable pain in patients with malignant disease. Recent pharmacokinetic studies have confirmed the rationale for regular administration of oral morphine and methadone but have revealed marked interindividual differences in the kinetics and metabolism which must be considered when titrating the oral dose according to the individual patient's need. Oral absorption of morphine in patients with malignant diseases is rapid, with peak plasma concentrations occurring at 20 to 90 minutes. Predose steady-state concentrations bear a constant relationship to dose, but vary considerably between individuals. The oral bioavailability is approximately 40% with marked patient-to-patient variations as a result of differences in presystemic elimination. The reported values for the volume of distribution range from 1.0 to 4.7 L/kg. Plasma protein binding is about 30%. The elimination half-life varies between 0.7 and 7.8 hours. Plasma clearance is approximately 19 ml/min/kg (5 to 34 ml/min/kg) and mostly accounted for by metabolic clearance. Studies in a few patients with malignant diseases treated regularly with daily doses of oral morphine ranging from 20 to 750mg indicate a linear relationship between the dose and trough concentration of morphine. Long term treatment with 10- to 20-fold increase of the oral dose over a period of 6 to 8 months does not seem to change the kinetics of oral morphine. The plasma concentrations of the main metabolite, morphine-3-glucuronide (M3G), exceed those of the parent drug by approximately 10-fold after intravenous administration and by 20-fold after oral administration. The relationship between the area under the plasma concentration-time curve (AUC) of morphine and the AUC of morphine-3-glucuronide remains constant during the development of tolerance upon long term treatment with increasing doses. Renal disease causes a significant increase in the mean plasma concentrations of morphine for 15 minutes after its administration, while mean values of terminal half-life and total body clearance are within the normal range. However, the glucuronidated polar metabolite morphine-3-glucuronide rises rapidly to high concentrations which persist for several days. Chronic liver disease causes an increase in the bioavailability of oral morphine but no, or only a slight reduction in the intravenous clearance. The elimination half-life and volume of distribution are within the normal range.(ABSTRACT TRUNCATED AT 400 WORDS)     

Pharmacokinetics of α-dihydroergocriptine in rats after single intravenous and single and repeated oral administrations

The pharmacokinetics of α-dihydroergocriptine methane sulphonate in rats were investigated using an HPLC method for the detection of unchanged α-dihydroergocriptine (DHEK) in plasma, organs (kidneys, heart, lungs, spleen, liver, and brain), and urine. The plasma profile of DHEK obtained after intravenous administration at a dose of 5 mg kg^?1 (as base) of DHEK methane sulphonate showed a three compartment pharmacokinetic model with an elimination half-life of 6.78 h. The kinetics of DHEK after a single oral administration at a dose of 20 mg kg^?1 (as base) showed two peaks: the second peak, at about 6 h, was probably due to an enterohepatic cycle. The disposition of DHEK consisted of an absorption half-life of 0.02 h, a distribution half-life of 2.15 h and an elimination half-life of 5.83 h. The pharmacokinetics of DHEK, after repeated oral administrations at the same dose, were similar to those after a single oral administration. The absolute bioavailability was 4.14% after a single oral administration and 3.95% after repeated oral administrations. The analysis of the organs showed that DHEK was rapidly absorbed and distributed in all tissues, mostly in lungs, kidneys, and liver, but it is interesting to observe that it also reached the brain. After repeated oral administrations plasma and tissue concentrations were similar to those obtained after a single administration; therefore it is possible to exclude the onset of autoinduction or accumulation phenomena of DHEK in rats' organs. Urinary excretion of the unchanged drug was low (0.38% of the administered dose in the intravenous route and 0.04% in the oral route), being in agreement with a low oral bioavailability and a rapid and extensive metabolism (first-pass effect).     

Pharmacokinetics of the diastereomers of arteether, a potent antimalarial drug, in rats

The pharmacokinetics of alpha- and beta- diastereomers of arteether, a potent erythrocytic schizontocidal agent, and their active metabolite dihydroartemisinin were studied in male Sprague-Dawley rats after oral, intramuscular and intravenous administrations. Oral and intramuscular studies were carried out at three dose levels at 9, 17.5 and 30 mg kg(-1). The ratio of alpha- and beta-isomers was maintained at 30:70% w/w in the formulations used for the study. The average oral bioavailabilities of alpha-and beta-isomers, relative to intramuscular administration, were 9.6% and 3.8%, respectively, and the average in vivo alpha- to beta- ratio was 2.5. Following intravenous and intramuscular administrations the in vivo alpha- to beta- ratios were 0.7 and 0.9, respectively. The beta-isomer of arteether was characterized by a longer elimination half-life and a relatively larger volume of distribution than the alpha-isomer, suggesting that beta-arteether may be responsible for the prolonged in vivo schizontocidal activity. The alpha-isomer was absorbed rapidly after oral and intramuscular administrations and showed higher peak plasma concentrations but possessed a relatively shorter half-life. There was an apparent lack of linearity observed in terms of dose and AUCs for both alpha- and beta-arteether after oral and intramuscular administrations, suggesting nonlinear dose dependent pharmacokinetics at the dose levels studied. The rate and extent of conversion of arteether isomers to dihydroartemisinin was highest with oral and intravenous administration and least with intramuscular indicating that the intramuscular route of administration of the isomeric mixture may be more beneficial for malarial chemotherapy.     

Pharmacokinetics of idarubicin (4-demethoxydaunorubicin; IMI-30; NSC 256439) following intravenous and oral administration in patients with advanced cancer.

The plasma pharmacokinetics of idarubicin (4-demethoxydaunorubicin) were studied in 20 patients with advanced malignant disease after intravenous (21 occasions) and oral (14 occasions) administration. Idarubicin plasma concentrations were measured by high performance liquid chromatography with fluorescence detection. Pharmacokinetic parameters calculated for the intravenous plasma drug concentration, time data revealed a terminal half-life of 12.9 +/- 6.0 h (mean +/- s.d.), clearance 98.7 +/- 47.3 1 h-1 m-2 and volume of distribution 1533 +/- 536 1 m-2. A bi-exponential equation corresponding to a two compartment open model best fitted the data. Half-life and clearance were not significantly different following oral administration. Bioavailability of oral idarubicin was 0.29 +/- 0.20 (mean +/- s.d.). There was a wide range of bioavailability between and within subjects. Plasma concentrations of idarubicinol (the only metabolite detected) rapidly exceeded those of the parent drug, and exposure to this metabolite was greater than to the parent drug. The mean half-life of idarubicinol was not significantly different after i.v. (63.1 +/- 28.2 h) and oral (45.8 +/- 16.0 h) administration. Much larger amounts of this metabolite were formed following the oral route of administration. This may have implications for the clinical use of this drug as idarubicinol may have appreciable cytotoxic activity.     

Pharmacokinetics of leucovorin calcium after intravenous, intramuscular, and oral administration

The pharmacokinetics of leucovorin was evaluated after intravenous, intramuscular, and oral administration in a randomized crossover study of 37 healthy men. A single 25-mg dose of leucovorin calcium was administered intravenously, intramuscularly, or orally to the subjects. Blood samples were obtained immediately before and at 13 time points up to 24 hours after the leucovorin dose. The three treatment phases were separated by one-week intervals. Bioavailability was assessed by measuring over 24 hours the blood concentrations of total folates, the parent compound 5-formyltetrahydrofolate, and the metabolite 5-methyltetrahydrofolate, using differential microbiologic assays with Lactobacillus casei and Streptococcus faecalis. Both intravenous and intramuscular administration produced rapid increases in serum concentrations of biologically active folates; these rises were sustained over time and were still detectable at 24 hours after drug administration. The bioavailability of intravenous and intramuscular doses was comparable based on area under the serum concentration-time curve, although for intramuscular administration, the peak concentration was lower and the time to peak concentration was longer. The initial rise in serum folate with intravenous and intramuscular dosing represented 5-formyltetrahydrofolate; this fell concomitantly with the appearance of 5-methyltetrahydrofolate. Oral leucovorin was 92% bioavailable compared with intravenous administration and produced a predictably different pattern of circulating folates, 5-methyltetrahydrofolate being the predominant form. Terminal elimination half-life, apparent volume of distribution, and clearance of total folate were not significantly different among the three treatments.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics and bioavailability of intravenous,oral, and rectal nitrazepam in humans

The pharmacokinetics and bioavailability of nitrazepam following intravenous, oral (tablet), and rectal (solution) administration were studied in seven healthy, young male volunteers. Nitrazepam plasma concentrations were determined by electron-capture GLC; pharmacokinetic evaluations were made by compartmental analysis (NONLIN) and compared with the results obtained by a less stringent modelling of the data. The plasma concentration-time profile was similar for all three routes of administration. Mean kinetic parameters as obtained by compartmental analysis of i.v. nitrazepam were: distribution half-life 17 min; volume of distribution after equilibrium 2.14 liters/kg; total plasma clearance 61.6 ml/min; elimination half-life 29.0 h. The mean protein unbound fraction of nitrazepam in plasma was 12.3% and the clearance of the unbound fraction was 506 ml/min. Absorption of oral nitrazepam started after the elapse of a lag time (mean value 12 min) and occurred as an apparent first-order process in all but one subject, with a mean absorption half-life of 16 min. Distribution and elimination half-lives were comparable with those following i.v. administration. Following rectal administration of the nitrazepam solution, rapid first-order absorption occurred with a mean lag time of 4 min and a mean absorption half-life of 9 min. Peak times (median 18 min) were significantly shorter than following oral administration (median 38 min), but there was little difference in peak concentrations. The distribution half-life was similar to i.v. and oral administration, but the elimination half-lives were longer with a mean value of 33.1 h. Following i.v. administration a good agreement was found between the results obtained by compartmental analysis using NONLIN and those obtained by a less stringent modelling of the data. Following oral and rectal administration, a good agreement between the two procedures was found for the elimination half-life; estimation of bioavailability, however, was higher by compartmental analysis. The mean bioavailability data showed that absorption is complete when nitrazepam is given orally and almost 20% lower when it is given rectally, but considerable interindividual differences were observed.     

Variable bioavailability of papaverine

The plasma concentration curves of papaverine have been studied in nine healthy males and seven patients after administration of single intravenous (80 mg) and oral (80 mg) doses. The bioavailability of the drug was highly variable with a mean of 28% (range 5-99%) but reproducible within the same individual (4 of the volunteers) after a repeated (80 mg) oral dose. The calculated half-life after intravenous administration ranged between 1.2-6.6 hours (mean 3.0). The mean apparent volume of distribution was 3.1 l/kg and the mean total plasma clearance was 836 ml/min. It is concluded that papaverine shows an unacceptable inter-individual variation in the bioavailability after oral administration of 80 mg tablets.     

Pharmacokinetics of [14C]ciclesonide after oral and intravenous administration to healthy subjects

BACKGROUND: Ciclesonide is a novel inhaled corticosteroid developed for the treatment of asthma. OBJECTIVE: To investigate the extent of oral absorption and bioavailability of ciclesonide referenced to an intravenous infusion. This information provides an estimate for the contribution of the swallowed fraction to systemic exposure to ciclesonide after oral inhalation. METHODS: In a randomised crossover study, six healthy male subjects (age range 19-40 years) received single doses of 6.9 mg (oral administration) and 0.64 mg (intravenous administration) of [14C]ciclesonide, separated by a washout period of at least 14 days. Total radioactivity was determined in whole blood, plasma, urine and faeces. Serum concentrations of ciclesonide and its major metabolite, the pharmacologically active desisobutyryl-ciclesonide (des-CIC), were determined in serum by high-performance liquid chromatography with tandem mass spectrometry detection. RESULTS: After a 10-minute intravenous infusion, the mean half-life for total radioactivity was 45.2 hours. Elimination of des-CIC was fast with a mean elimination half-life of 3.5 hours. After oral administration, the mean half-life for total radioactivity was 27.5 hours. On the basis of a comparison of dose-normalised areas under the curve of total plasma radioactivity versus time, 24.5% of orally administered [14C]ciclesonide was absorbed. The parent compound ciclesonide was not detected in any of the serum samples after oral administration; serum concentrations of des-CIC were mostly near or below the lower limit of quantification. Thus, systemic bioavailability for des-CIC is <1% and the absolute bioavailability of ciclesonide is even less than this. [14C]Ciclesonide showed no retention in red blood cells. The mean cumulative excretion of total radioactivity was almost complete by 120 hours after oral and intravenous administration. Faecal excretion was the predominant route of excretion for total radioactivity after both routes of administration. Single oral and intravenous administration of ciclesonide was well tolerated. CONCLUSIONS: Because of an almost complete first-pass metabolism, ciclesonide is undetectable in serum after oral administration. Thus, any ciclesonide swallowed after oral inhalation does not contribute to systemically available ciclesonide or to its active metabolite. Drug-related metabolites are excreted mainly via the faeces, and overall recovery of administered radioactivity is virtually complete after an extended sample collection period.     

Estimation of the absolute bioavailability of rivastigmine in patients with mild to moderate dementia of the Alzheimer's type

OBJECTIVE: To investigate the bioavailability of rivastigmine, an approved therapy for patients with mild to moderate dementia of the Alzheimer's type, at the highest approved single dose of 6 mg. DESIGN AND SETTING: Randomised, two-period crossover, single-centre, non-blinded, inpatient study.Patients and participants: Eleven patients (five females and six males) with mean age 69.5 years. METHODS: The 6 mg oral dose was compared with a 2 mg intravenous dose of rivastigmine infused over a 1-hour period. Plasma concentrations of rivastigmine and its metabolite NAP 226-90 were measured with a gas chromatographic/mass spectrometric method. RESULTS: Following oral administration of a single 6 mg capsule, rivastigmine is rapidly absorbed with an average time to peak plasma concentration of about 1 hour and an average peak concentration of about 25.6 g/L. By a noncompartmental approach, the absolute bioavailability of the 6 mg oral dose of rivastigmine was 71.7% when compared with a 2mg intravenous infusion normalised for dose. By using a population pharmacokinetic model with Michaelis-Menten elimination, absolute bioavailability was estimated at 60.2%. The average terminal elimination half-life of rivastigmine ranged from 1.4 to 1.7 hours for both treatments. Plasma concentrations of the major metabolite, NAP 226-90, formed by the hydrolysis of rivastigmine by cholinesterase are lower than those of the parent compound following oral and intravenous administration. CONCLUSION: A noncompartmental approach and a compartmental approach based on a population pharmacokinetic model with Michaelis-Menten elimination yielded comparable values, 71.7% and 60.2% respectively, for the absolute bioavailability of a single 6 mg oral dose of rivastigmine. Comparison with previous studies confirmed that the oral form of the drug exhibits increased bioavailability with increasing dose, consistent with its nonlinear pharmacokinetics..     

Systemic availability of oral verapamil and effect on PR interval in man.

1 The plasma levels of verapamil and its major metabolite norverapamil were related to its effect as a Ca-antagonist on atrio-ventricular (AV) conduction, judged from prolongation of the PR interval in six normal volunteers. 2 Intravenous administration (0.1 mg kg-1) was compared to oral administration (120 mg) in each subject. 3 Intravenous verapamil showed a mean distribution half-life (alpha) of 8.5 min and elimination half-life (beta) of 2.0 h. The volume of distribution was about 112.1. Oral dosage gave an elimination half-life of 2.7 h, and a norverapamil half-life which averaged 4.6 h. The bioavailability of the oral dose averaged 22% (17 to 29%). 4 After the oral dose the percentage change in PR interval in the five appropriate subjects correlated significantly with the log plasma verapamil level (r = 0.732), but not with the log plasma norverapamil level (r = 0.078); norverapamil could not be detected after the intravenous dose. One subject developed Wenckebach type second degree AV block after each dose.