Pharmacokinetics of ketotifen after oral administration to healthy male subjects.

The pharmacokinetics of 2 mg ketotifen from four different oral dosage forms were examined in two randomized, balanced cross-over studies. Forty healthy male subjects participated. Each of 20 subjects received two capsule formulations and each of the other 20 subjects received two syrup formulations. Ketotifen concentrations in plasma were determined by a modified GC-MS method. The limit of quantitation was 40 pg ml-1. Inter-day precision and accuracy calculated from quality control samples were 16.3 per cent (-1.9 per cent), 19.8 per cent (+4.5 per cent) and 23.6 per cent (+5.9 per cent) at plasma concentration levels of 86 (n = 18), 215 (n = 19) and 343 (n = 18) pg ml-1, respectively. Ketotifen was rapidly absorbed from all dosage forms reaching Cmax in the order of 400 pg ml-1 after the syrup formulations and 300 pg ml-1 after the capsule formulations within 2 to 4 h. The syrup formulations showed a significantly more rapid rate of absorption as assessed by Tmax. No significant differences in extent of absorption between dosage forms were observed. The terminal elimination half-life of ketotifen varied between subjects from 7 to 27 hours with a mean of about 12 h. The minor pharmacokinetic difference between dosage forms observed in this study is unlikely to be of clinical significance.     

Pharmacokinetics of hydroflumethiazide during repeated oral administration to healthy subjects

Summary The pharmacokinetics of hydroflumethiazide (HFT) were investigated during repeated oral administration of 100 mg (302 µmoles), every 24 h for 7 consecutive days, to 6 healthy male volunteers. HFT and a metabolite, 2,4-disulfamyl-5-trifluoromethylaniline (DTA), were determined by TLC and spectrofluorodensitometry. Steady state had been reached on the fourth day (judged by urinary excretion rates of HFT and DTA). The mean biological half-life of HFT was 6.85 h (range 5.1–8.7), and the mean half-life of DTA was 17.7 h (range 11.1–21.0). The accumulation factors (expressed as relative increase in urinary excretion rates 12–24 h after doses) were 1.15 for HFT and 2.28 for DTA, which is in reasonable agreement with what can be predicted from the half-lives. The mean fraction of the dose excreted in urine as HFT was 0.652 (range 0.53–0.73) and as DTA 0.049 (range 0.035–0.073), during one dosage interval at steady state. The mean renal plasma clearance of HFT was 0.3561 · h^–1 · kg^–1 (range 0.310–0.402), and the mean instant volume of distribution of HFT was 3.491 · kg^–1 (range 2.78–4.76). DTA was not detected in plasma, but reached a concentration in the red cell fraction which was higher than that of HFT during most of the dosage interval. DTA was therefore excreted in urine with a longer apparent t_1/2 and it accumulated to a greater degree than the parent drug.     

Pharmacokinetics and bioavailability of omeprazole after single and repeated oral administration in healthy subjects.

1. Ten healthy subjects were given 20 mg omeprazole EC (enteric coated) granules once daily for 8 days. An i.v. tracer dose of [14C]-omeprazole was given simultaneously with the first and last oral doses and blood sampling was performed thereafter. In order to study the extent of absorption at minimal acid exposure, a single dose of 20 mg omeprazole was also given as a buffered solution, before and after the treatment with EC granules. 2. Kinetic parameters of omeprazole after the i.v. tracer dose were unchanged on repeated dosing while AUC increased by approximately 40% for the solution and 60% for the EC granules. 3. The increased AUC is caused by an increased systemic availability, which may be explained by a decreased first-pass elimination during repeated treatment and/or by a reduced degradation of omeprazole in the stomach secondary to the profound decrease in intragastric acidity caused by the drug. 4. The implication of these findings is that the antisecretory effect of therapeutic doses of omeprazole must be studied during repeated administration and not judged from studies using single doses only.     

Pharmacokinetics of eltoprazine in healthy male subjects after single dose oral and intravenous administration.

The kinetics, safety and tolerability of eltoprazine hydrochloride were studied in an open, cross-over, partially randomised design after single oral (8 mg) and intravenous (3 and 8 mg) doses to 12 healthy male subjects. After intravenous administration, the mean t1/2 ranged from 7 to 9 h, the MRT was 11 h, CL was 487 +/- 148 (3 mg dose) and 471 +/- 56 (8 mg dose) ml kg-1 h-1, while CLR was 226 +/- 124 (3 mg dose) and 189 +/- 38 (8 mg dose) ml kg-1 h-1. The Vss was 3.3 +/- 0.7 (3 mg dose) and 3.8 +/- 0.5 (8 mg dose) 1 kg-1. Cumulative renal excretion was 40%. The AUC and the cumulative urinary excretion were directly proportional to dose within the range of 3-8 mg. Values of tmax varied from 1 to 4 h after oral administration. The mean Cmax value was 24 ng ml-1 after an oral dose of 8 mg. The plasma elimination half-life after oral administration was 9.8 +/- 3.9 h. Absolute oral bioavailability was 110 +/- 32%. Dose-dependent somnolence was observed.     

Pharmacokinetics of esomeprazole after oral and intravenous administration of single and repeated doses to healthy subjects

OBJECTIVE: To study the pharmacokinetics of esomeprazole, one of the optical isomers of omeprazole, after 20 mg or 40 mg single and repeated oral and intravenous administration to healthy subjects. The main metabolites of esomeprazole were also assessed after the 40-mg oral dose. METHODS: In two separate studies, 16 healthy male subjects and 16 healthy male and female subjects received intravenous doses of 20 mg and 40 mg esomeprazole, respectively, on the first investigation day. After a washout period of 5-14 days, the same doses (20 mg as a solution and 40 mg as a capsule) were given orally for 5 days and then again intravenously on day 6. Blood samples for determination of esomeprazole and its metabolites were collected 12 h or 24 h post-dose and were analysed using normal-phase liquid chromatography with ultraviolet (UV) detection. Pharmacokinetic parameters of esomeprazole and its metabolites were estimated using non-compartmental analysis. Geometric means and ratios of the geometric means together with 95% confidence intervals (CI) of the pharmacokinetic parameters were calculated using analysis of variance (ANOVA). RESULTS: Plasma clearance (CL) of esomeprazole decreased from 22 l/h to 16 l/h and from 17 l/h to 9 l/h following repeated dosing of 20 mg and 40 mg, respectively. Total area under the plasma concentration-time curve (AUC) increased (from 1.34 micromol x h/l to 2.55 micromol x h/l) with absolute bioavailability (F) being 50% on day 1 and 68% on day 5 after the 20-mg oral dose. AUC increased (from 4.32 micromol x h/l to 11.21 micromol x h/l) with F being 64% on day 1 and 89% on day 5 after the 40-mg oral dose. The plasma levels for esomeprazole sulphone were substantially higher on day 5 than on day 1, while those for 5-hydroxy esomeprazole were marginally higher on day 5 than on day 1 following repeated oral dosing of 40 mg esomeprazole. No side effects attributable to esomeprazole were noticed. CONCLUSION: The increased AUC of esomeprazole with repeated dosing is probably due to a combination of a decreased first-pass elimination and a decreased systemic clearance.     

单剂量口服他达拉非在中国健康男性受试者的药代动力学和安全性

目的 研究中国健康男性受试者单剂量口服他达拉非的药代动力学和安 全性。方法 用双盲随机安慰剂对照三交叉设计。在3个周期随机单次服用 他达拉非10,20 mg或安慰剂,采集静脉血,用液相色谱-质谱法测定血药浓度 并计算药代动力学参数。结果 单次服用他达拉非10,20 mg后的主要药代动 力学参数AUC0-t分别为3750和7180 ng·h·mL-1;AUC0-∞分别为3820和 7370 ng·h·mL-1;Cmax分别为172和274 ng·mL-1;tmax分别为3．00和4．00 h;CL／F分别为2．61和2．71 L·h-1;V／F分别为67．6和73．2 L。结论 他达 拉菲在10-20 mg,中国健康男性受试者较安全,且AUC与剂量呈正相关。     

连续口服盐酸噻氯匹定片在健康人体的药代动力学

目的研究连续口服盐酸噻氯匹定片(抗血栓药)在健康人体的药代动力学。方法12名男性健康志愿者连续口服噻氯匹定片,每次250mg,每日2次。第11日按照预定时间点采血,用LC-MS-MS方法测定血浆稳态血药浓度,并求算其药代动力学参数。结果t1/2为(115±13.8)h,AUC0-21d为(24.48±10.02)μg.h.mL-1,tmax为(1.8±0.6)h,Cmax为(1303±428)ng.mL-1,Cmin为(235±107)ng.mL-1,Cav为(541±194)ng.mL-1,AUCss为(6.49±2.32)μg.h.mL-1,CLss为(48.1±33.7)L.h-1。结论连续口服盐酸噻氯匹定,吸收迅速,消除半衰期较单剂量大大延长;个体变异小。     

Pharmacokinetics of piperaquine after single and multiple oral administrations in healthy volunteers

The aim of this work was to study the pharmacokinetics of piperaquine in healthy volunteers. Healthy volunteers received piperaquine and tablets of Artekin by oral administration. The plasma samples were analyzed for piperaquine by liquid-liquid extraction and determined by HPLC-UV. The results demonstrated that the plasma drug concentration-time curves of single and multiple dose of piperaquine were fitted to a two-compartment open model. The pharmacokinetics parameters of piperaquine alone in a single dose were: t(1/2(beta))=(317.2-/+126.6)h, AUC(0-->infinity)=(44293-/+12636)h x ng/ml, V(d)=(9490.9-/+2161.9)ml/kg, and Cl=(22.83-/+9.83)ml/h/kg. In Artekin in a single dose these parameters were: t(1/2(beta))=(302.8-/+180.7)h, AUC(0-->infinity)=(46419-/+13670)h x ng/ml, V(d)=(10188.6-/+3520.3)ml/kg, and Cl=(25.48-/+10.89)ml/h/kg, while in Artekin in multiple doses they were: t(1/2(beta))=(298.9-/+101.9)h, AUC(0-->infinity)=(227692-/+56294)h x ng/ml, V(d)=(5031.5-/+1097.8)ml/kg, Cl=(11.91-/+3.046)ml/h/kg, respectively. The absorption and distribution of piperaquine were quick while the elimination was quite slow. There were significant differences in the pharmacokinetics parameters of piperaquine in Artekin between a single dose and multiple doses (p<0.001), suggesting that piperaquine might accumulate in vivo and that attention should be given to its possible adverse drug reactions in clinical treatment.     

Pharmacokinetics of pantoprazole following single intravenous and oral administration to healthy male subjects

Summary The plasma pharmacokinetics of pantoprazole have been investigated following single intravenous infusion and single oral administration at a dose of 40 mg to 12 healthy male subjects in a randomised cross-over study. Both treatments were generally well tolerated and no relevant compound-related adverse events were noted. The plasma pharmacokinetics of pantoprazole following intravenous infusion in this group of subjects were characterised by a total plasma clearance of 0.13 l·h⁻¹·kg⁻¹ and apparent terminal elimination half-life 1.9 h. The apparent volume of distribution estimated at steady state (0.171·kg⁻¹) was compatible with the localization of a major fraction of the compound in extracellular water. Following oral administration as an enteric-coated tablet formulation, a variable onset of absorption was followed by rapid attainment of maximum plasma concentrations of pantoprazole. Pantoprazole was well absorbed following oral administration; the absolute systemic bioavailability of the compound was estimated as 77% (95% CI, 67 to 89%).     

Pharmacokinetics of antofloxacin hydrochloride in healthy male subjects after multiple intravenous dose administration

1. The purpose of the study was to evaluate pharmacokinetic characteristics of antofloxacin hydrochloride, a new fluoroquinolone antibiotic, during a multiple, intravenous dosing regimen.

2. Twelve healthy, Chinese male volunteer subjects were each given 300?mg of antofloxacin by intravenous infusion once daily for 7 days. Blood and urine samples were taken at designated time points for analysis of antofloxacin concentration by high-performance liquid chromatography (HPLC). Safety and tolerability were assessed by evaluation of subject complaints, vital signs, electrocardiograms, electroencephalograms, clinical chemistry parameters, haematology and urinalysis and prothrombin time.

3. The serum steady concentration of antofloxacin was obtained in 96?h after the administration of a daily intravenous dose of 300?mg of the drug. In the present study, the following pharmacokinetic parameters after 7 days of treatment with antofloxacin were determined to be: C_max 3.81?±?0.66?mg/L, C_min 0.85?±?0.19?mg/L, AUC_0–24 60.51?±?8.30?mg/L·h, C_av 2.52?±?0.35?mg/L, PTF 87.45?±?3.37%, t_1/2β 20.34?±?1.88?h. The C_max and AUC_0–24 after 7-day treatment were both higher than after the first dose (by 43% and 110%, respectively). The cumulative urinary elimination of antofloxacin within 96?h after the last dose was about 56%.

4. During the study, there were neither subject complaints nor significant adverse clinical findings.

5. Antofloxacin, administered intravenously as a single, daily 300?mg dose for 7 days, demonstrated favourable pharmacokinetic characteristics and tolerability. The results of this study indicate that antofloxacin hydrochloride is suitable for further clinical study.

     

Pharmacokinetics of antofloxacin hydrochloride in healthy male subjects after multiple intravenous dose administration

The purpose of the study was to evaluate pharmacokinetic characteristics of antofloxacin hydrochloride, a new fluoroquinolone antibiotic, during a multiple, intravenous dosing regimen. Twelve healthy, Chinese male volunteer subjects were each given 300?mg of antofloxacin by intravenous infusion once daily for 7 days. Blood and urine samples were taken at designated time points for analysis of antofloxacin concentration by high-performance liquid chromatography (HPLC). Safety and tolerability were assessed by evaluation of subject complaints, vital signs, electrocardiograms, electroencephalograms, clinical chemistry parameters, haematology and urinalysis and prothrombin time. The serum steady concentration of antofloxacin was obtained in 96?h after the administration of a daily intravenous dose of 300?mg of the drug. In the present study, the following pharmacokinetic parameters after 7 days of treatment with antofloxacin were determined to be: C(max) 3.81?±?0.66?mg/L, C(min) 0.85?±?0.19?mg/L, AUC(0-24) 60.51?±?8.30?mg/L·h, C(av) 2.52?±?0.35?mg/L, PTF 87.45?±?3.37%, t(1/2)β 20.34?±?1.88?h. The C(max) and AUC(0-24) after 7-day treatment were both higher than after the first dose (by 43% and 110%, respectively). The cumulative urinary elimination of antofloxacin within 96?h after the last dose was about 56%. During the study, there were neither subject complaints nor significant adverse clinical findings. Antofloxacin, administered intravenously as a single, daily 300?mg dose for 7 days, demonstrated favourable pharmacokinetic characteristics and tolerability. The results of this study indicate that antofloxacin hydrochloride is suitable for further clinical study.     

Pharmacokinetics and metabolism of the antimalarial piperaquine after intravenous and oral single doses to the rat

This study aimed to evaluate the pharmacokinetic properties of piperaquine in the rat after intravenous and oral administration, and to identify and characterize the main piperaquine metabolites in rat plasma, urine, faeces and bile after intravenous administration. Male Sprague-Dawley rats were administered piperaquine as an emulsion orally or as a short-term intravenous infusion. Venous blood for pharmacokinetic evaluation was frequently withdrawn up to 90 h after dose. Urine, bile and faeces were collected after an infusion in rats kept in metabolic cages or in anesthetized rats. Pharmacokinetic characterization was done by compartmental modeling and non-compartmental analysis using WinNonlin. Piperaquine disposition was best described by a 3-compartment model with a rapid initial distribution phase after intravenous administration. The pharmacokinetics of piperaquine was characterized by a low clearance, a large volume of distribution and a long terminal half-life. Piperaquine displayed a low biliary clearance and less than 1% of the total dose was recovered in urine. The absolute oral bioavailability was approximately 50%. The main metabolite after intravenous administration of piperaquine was a carboxylic acid product identical to that reported in humans. The similarity with results in humans indicates the rat to be a suitable species for nonclinical in vivo piperaquine studies.     

Pharmacokinetics of telmisartan in healthy Chinese subjects after oral administration of two dosage levels

To study the pharmacolkinetics of telmisartan in healthy Chinese male subjects after oral administration of two dosage levels, 36 healthy subjects were divided into two groups and given a single oral dose of 40 or 80 mg telmisartan (CAS 144701-48-4, MicardisPlus). A sensitive liquid chromatography-tandem mass spectrometry method (LC-MS-MS) was used for the determination of telmisartan in plasma. Both, a non-compartmental and compartmental method were used for analysis of parameters of kinetics. The main pharmacokinetic parameters of the 40 mg and 80 mg regimen group were as follows: t(max) (1.76 +/- 1.75) h, (1.56 +/- 1.09) h, C(max) (163.2 +/- 128.4) ng/mL, (905.7 +/- 583.4) ng/mL, t1/2 (23.6 +/- 10.8) h, (23.0 +/- 6.4) h, AUC(o-t) (1456 +/- 1072) ng x h/mL, (6759 +/- 3754) ng x h/mL, AUC(o-infinity (1611 +/- 1180) ng x h/mL, (7588 +/- 4661) ng x h/mL, respectively. After dose normalization, there was significant difference for main pharmacokinetic parameters C(max) AUC(o-t) and AUC(o-infinity) between two dosage level groups. The plasma concentration-time profile of telmisartan was characterized by a high degree of inter-individual variability and the disposition of telmisartan in healthy Chinese subjects was dose-dependent. The pharmacokinetic parameters C(max) and AUC(o-inifinity) of the 80 mg regimen group increased to about 5-fold compared to that of the 40 mg regimen group, but there was no significant difference for t(max) and t1/2 between the two dose groups.     

Pharmacokinetics of tenoxicam after oral administration in healthy human subjects of various single doses

Single oral dose pharmacokinetics of tenoxicam in the dose range intended for therapeutic application of the drug have been defined in healthy human subjects. Twelve male volunteers were given, in random fashion, oral administration of 10, 20 or 40 mg of tenoxicam. Plasma drug levels were determined by a standard HPLC method with U.V. detection. Model-independent analysis showed the clearance, elimination half-life and apparent volume of distribution to be independent of dose with mean values of 0.096 L/h, 76 h and 9.2 L respectively. Interindividual variation was six-fold and individual variation less than two-fold. Similar values for kinetic parameters were obtained by model-dependent methods. The pharmacokinetics of oral tenoxicam were linear in the 10-40 mg dose range and the single dose data predict five-fold accumulation for once daily administration.     

Pharmacokinetics of sarizotan after oral administration of single and repeat doses in healthy subjects

OBJECTIVE: Sarizotan is a 5-HTIA receptor agonist with high affinity for D3 and D4 receptors. Here we report the pharmacokinetic and tolerability results from four Phase 1 studies. MATERIALS: Two single-dose (5 -25 mg, n = 25, 0.5 - 5 mg, n = 16) and two multiple-dose (10 and 20 mg b.i.d., n = 30, 5 mg b.i.d., n = 12) studies with orally administered sarizotan HCl were carried out in healthy subjects. METHODS: Plasma sarizotan HCl concentrations were measured using a validated HPLC method and fluorescence or MS/MS detection. Pharmacokinetic parameters were obtained using standard non-compartmental methods. RESULTS: Sarizotan was rapidly absorbed, group-median times to reach maximum concentration (tmax) ranged from 0.5 -2.25 h after single doses and during steady state. Maximum plasma concentration (Cmax) and tmax were slightly dependent on formulation and food intake, whereas area under the curve (AUC) was unaffected by these factors. AUC and Cmax increased dose-proportionally over the tested dose range. Independently of dose and time, sarizotan HCl plasma concentrations declined polyexponentially with a terminal elimination half-life (t1/2) of 5 - 7 h. Accumulation factors corresponded to t1/2 values, and steady state was reached within 24 h. Plasma metabolite concentrations were considerably lower than those of the parent drug. The ratio metabolite AUC : parent drug AUC was time- and dose-independent for all three metabolites suggesting that the metabolism of sarizotan is non-saturable in the tested dose range. CONCLUSIONS: The pharmacokinetics of sarizotan were dose-proportional and time-independent for the dose range 0.5 -25 mg). The drug was well-tolerated by healthy subjects up to a single dose of 20 mg.     

健康男性多次口服爱地那非片的药代动力学和安全性

目的 研究中国男性健康受试者多次口服枸橼酸爱地那非片(治疗阴茎勃起功能障碍)的安全性和药代动力学.方法 27名受试者随机分为30、45和60 mg 3个剂量组,每组9人,试验期间严密观察临床症状体征和不良事件,用LC-MS/MS测定多次服药后血浆中的药物浓度,并计算药代动力学参数.结果 受试者多次口服枸橼酸爱地那非片30、45和60 mg后,其主要药代动力学参数:Cmax分别为(256.6±106.6)、(435.7±115.4)和(918.6±442.5)ng·mL-1;Cav分别为(57.2±26.1)、(95.0±28.9)和(247.6±137.0)ng·mL-1;tmax分别为(1.1±0.6)、(1.2±0.6)和(1.6±0.5)h;t1/2分别为(4.5±0.3)、(4.4±0.6)和(3.9±0.6)h;AUC0-24h分别为(1373.3±625.6)、(2280.1±693.6)和(5941.8±3288.4)ng·h·mL-1;AUC0-36h分别为(1405.9±650.2)、(2314.6±710.3)和(6039.9±3 338.4)ng·h·mL-1.药物不良反应主要为面色潮红、头痛或头晕等,程度均为轻度.结论 连续3天,每天1次,口服枸橼酸爱地那非30～60 mg对健康受试者是安全的,爱地那非在体内无明显蓄积;在30、45 mg时,Cmax和AUC0-t与剂量成比例增加;而在60 mg时,呈非线性药代动力学特征.     

Pharmacokinetics of acrylamide after oral administration in male rats

Acrylamide (AMD) is a commonly used industrial chemical. However, it produces a dying back type of peripheral neuropathy in animals and man. This study was performed to investigate the pharmacokinetics of AMD after oral administration at 50 mg/g ([1-(14)C]AMD) in male Sprague-Dawley rats. Absorption from the gastrointestinal tract was rapid and radioactivity was detected in blood 5 min post-administration. The peak plasma concentration occurred 38 min after administration and was equivalent to 47 μg/ml. The elimination pattern for plasma was fitted to a one-compartment model with 6 h half-life. However, in the blood the elimination pattern was fitted to a two-compartment model with 7.93 and 374 h for distribution and elimination phases, respectively. Tissue concentrations of radioactivity determined at 28 and 144 h post-administration differed substantially. After 28 h the highest activity was in the gastric content, followed by stomach, lung, bone marrow and skin, while after 144 h the order of total radioactivity was lung>bone marrow>esophagus. The activities in the rest of the organs in both experiments were very low. The excretion study revealed that the kidney is the major route of elimination and the majority of radioactivity in urine was excreted during the first 12 h. The feces contained approximately 10% of the administered dose after 144 h. This study indicated that AMD is rapidly absorbed from the rat's gastrointestinal tract, distributed and eliminated from the body. AMD bound but did not accumulate in the erythrocytes or the neural tissues.     

Pharmacokinetics of diazepam following multiple-dose oral administration to healthy human subjects

Six healthy subjects between the ages of 21 and 31 years received diazepam tablets orally at a dose of 5 mg t.i.d. atO, 5, and 10hr on days 1–13. On day 14, the dose was 5 mg at 0 and 5 hr and 15 mg at 10 hr. Subsequently, the dose was 15 mg once daily on days 15–24. Numerous plasma samples were obtained during the multiple-dose regimen, and appropriate equations were fitted to all the multiple-dose data. Diazepam absorption was satisfactorily described by a first-order process, with disposition characterized by a linear two-compartment open model. The harmonic mean absorption half-life was 32 min, and the harmonic mean terminal exponential half-life was 57hr. The mean apparent oral total drug plasma clearance was 22.7ml/hr/kg. Steady-state plasma levels of the primary metabolite, desmethyldiazepam, were reached after 5–8 days of dosing. Steady-state diazepam plasma concentration-time profiles suggested that once daily administration of the total daily dose at bedtime might be a satisfactory dosing regimen.     

Pharmacokinetics of pramiracetam in healthy volunteers after oral administration.

The pharmacokinetics of pramiracetam was assessed using an HPLC method after oral administration of two different formulations of 600 mg (a solution and a tablet) of pramiracetam to 11 fasting volunteers. The mean kinetic parameters were: t1 = 4.7 +/- 2.4 - 4.3 +/- 2.2 h, AUC = 57.6 +/- 43.6 - 47.2 +/- 33.9 micrograms h/ml, Cmax = 6.80 +/- 3.2 - 5.80 +/- 3.3 micrograms/ml for the solution and the tablet respectively. The plasma profile of pramiracetam proved to be not highly affected by the formulation, only that the absorption rate was faster after oral administration of the drug in solution than after administration as a tablet. The half-life was very variable between subjects [2-8 hours], but less variable within subjects and it was unaffected by the formulation.     

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.