Pharmacokinetics and absolute bioavailability of lansoprazole

Objective: In a crossover study 12 healthy volunteers received lansoprazole 15 mg or 30 mg orally, or 15 mg intravenously in randomized order as a single dose. Blood samples were taken and plasma levels of lansoprazole were determined using an HPLC method. The volunteers were phenotyped for the debrisoquine/sparteine and mephenytoin polymorphisms. Results: The total clearance was 517 ml⋅min⁻¹, and the absolute bioavailability was 91% for the 30-mg and 81% for the 15-mg enteric-coated formulation. The elimination half-life was about 1 h. No correlation of the plasma levels to the sparteine metabolic ratio was found, and no correlation to the mephenytoin type could be established, since all volunteers of the mephenytoin type were extensive metabolizers. Although considerable variation, inter- and intraindividually, was observed, the increase in c_max and AUC did not deviate from dose proportionality. The present galenic formulation ensures a high bioavailability after a single dose. Received: 24 March 1995/Accepted in revised form: 11 July 1995     

Comparative bioavailability of a cisapride suppository and tablet formulation in healthy volunteers

Summary The comparative bioavailability of cisapride as a 30 mg suppository and three 5 mg oral tablets was investigated in 12 non-smoking, healthy male volunteers. The two formulations were administered on two separate occasions following an overnight fast, according to a randomized cross-over design. The plasma concentration of cisapride was measured over 48 h after drug administration. The 30 mg suppository exhibited a mean time to the peak plasma concentration of 3.8 h, while the tablets showed a significantly earlier peak time of 1.5 h. The maximum plasma concentration of cisapride after the 30 mg suppository (50.3 ng · ml^–1) was significantly lower than after the tablets (74.3 ng · ml^–1). The AUCs following the two treatments did not differ significantly from each other.The comparative bioavailability of the 30 mg cisapride suppository in relation to the three 5 mg oral tablets was 85%, with a 95%-confidence interval of 67% to 102% (not adjusted for dose). Normalizing the mean AUC by dose, the relative bioavailability of the suppository was 43% of that of the tablet. The elimination half-life of cisapride was not significantly different following the administration of the two formulations (9.3 h for the suppository and 9.8 h for the tablet).     

The absolute bioavailability and metabolic disposition of the novel antimigraine compound zolmitriptan (311C90)

Aims Two open studies in healthy volunteers were conducted to determine the absolute bioavailability and metabolic disposition of zolmitriptan (311C90), a novel 5HT_1D agonist for the acute treatment of migraine. Methods After an initial test i.v. infusion, bioavailabilty was assessed by comparison of AUC after an i.v. infusion (3.5 mg) and an oral tablet (10 mg), in six men and six women using a randomised, crossover design. Disposition was studied by administration of a 25 mg capsule, labelled with 100 μCi []> ¹⁴C]-zolmitriptan, to five men and one woman on a single occasion. Results Zolmitriptan was well tolerated by both i.v. and oral routes. Adverse events were mostly mild, consistent with earlier studies and characteristic of this class of drug. Reports were similar in nature and number after both oral and iv dosing. Mean±s.d. oral bioavailability was 0.49±0.24 (0.38±0.16 in men and 0.60±0.28 in women). After oral dosing, C_max and AUC values in women were approximately double those in men. Relative to zolmitriptan concentrations, metabolite concentrations were higher after oral dosing than after i.v., and higher in men compared with women. Half-life was significantly longer after oral dosing (mean 22%, 95% CI 6–35%). Mean±s.d. values for CL, V_z and t_1/2,z after i.v. dosing (all subjects) were 8.7±1.7 ml min⁻¹ kg⁻¹, 122±32 l and 2.30±0.59 h respectively. Following administration of 25 mg [¹⁴C]-zolmitriptan, 91.5% of the dose was recovered in 7 days, 64.4±6.5% in urine and 27.1±6.0% in faeces. Less than 10% was recovered unchanged in urine, with 31.1±6.4% recovered as the inactive indole acetic acid metabolite. Most of the faecal material was unchanged zolmitriptan, representing unabsorbed drug. Plasma concentrations of [¹⁴C] were slightly higher than those of the summed concentrations of known analytes zolmitriptan, the active N-desmethyl metabolite (183C91), the inactive N-oxide (1652W92) and indole acetic acid (2161W92) metabolites, which accounted for 86% of total plasma radioactivity. No other significant metabilites were detected in plasma. Some minor additional metabolites were detected in urine, none of which contributed more than 5% of the dose. Conclusions The data suggest that zolmitriptan undergoes first-pass metabolism and this is more extensive in men than in women. Zolmitriptan has suitable bioavailabilty for an acute oral migraine treatment and there are no significant unidentified metabolites in man.     

Relative bioavailability of a complex Metformin plus glibenclaminde formulation in male volunteers

复方盐酸二甲双胍片的相对生物利用度与药动学研究@刘晓颖$Research Center of Medical Sciences, Guangdong Provincial People's Hospital!Guangzhou 510080, Guangdong,China @陈铁锋$Research Center of Medical Sciences, Guangdong Provincial People's Hospital!Guangzhou 510080, Guangdong,China @杨敏$Research Center of Medical Sciences, Guangdong Provincial People's Hospital!Guangzhou 510080, Guangdong,China @余细勇$Research Center of Medical Sciences, Guangdong Provincial People's Hosp…     

Evaluation of a novel method to estimate absolute bioavailability of drugs from oral data

The goal of this investigation was to evaluate the performance of a novel method allowing estimation of absolute bioavailability from oral data only. In contrast to the traditional method, which compares areas under the drug concentration time curves after oral and intravenous administration in subjects with normal renal function, the novel method uses total and renal clearance values following oral administration from subjects with varying renal functions to estimate bioavailability. The novel method can also provide estimates for nonrenal clearance.Published data on total clearance and renal clearance of drugs obtained from subjects with variable renal functions were collected, the novel method applied, estimates of bioavailability and nonrenal clearance obtained and compared with reported estimates by the traditional methods. In addition computations were performed to assess various factors that could possibly affect the reliability of the novel method. The results indicated that the novel method provides accurate estimates for bioavailability of drugs meeting the prerequisites: linear kinetics, predominant renal excretion in normals, absence of metabolic polymorphism and independence of bioavailability and nonrenal clearance from renal function. The average (standard deviation) of the prediction error and bias of the bioavailability estimates by the novel method was 7.8 (6.0) and -1.4 (9.8)%, respectively. The estimates for nonrenal clearance by the novel method were less accurate. The computations confirmed that the estimates by the novel method are sensitive to renal-function dependent changes in nonrenal clearance and bioavailability and also depend on the extent of renal excretion of a drug. In conclusion, the novel method's main use is to diagnose absence or presence of changes in bioavailability and non-renal clearance of drugs in populations with varying renal function.     

Pharmacokinetics and absolute bioavailability of salbutamol in healthy adult volunteers

Summary Salbutamol was administered to sixteen healthy male volunteers intravenously and by mouth in liquid, tablet, and capsule form using a Latin-Squares design. Pharmacokinetic parameters from intravenous data were similar to previously reported values obtained with oral administration, with a mean terminal half-life of 3.8 h and a mean clearance of 439 ml·min⁻¹·1.73 m⁻². Peak plasma concentrations of 10–20 ng·ml⁻¹ were obtained 1–3 h following oral administration. The absolute bioavailability of each of the oral preparations was 44%. While statistically significant differences in lag time and time to peak concentration were noted among the various oral preparations, the drug is rapidly absorbed in all three dosage forms and the observed differences are unlikely to be of clinical significance.     

没食子酸在大鼠体内的药物动力学及生物利用度

目的建立大鼠血浆中没食子酸的高效液相测定方法;研究大鼠灌胃与静脉给药后没食子酸的药物动力学过程及生物利用度。方法分别灌胃和静脉给予大鼠没食子酸,不同时间点采血,样品经甲醇沉淀蛋白后,采用Phenomenex C18(250 mm×4.6 mm,4μm)色谱柱,甲醇-体积分数为0.5%的冰醋酸水溶液(体积比为7∶93)为流动相,流速为1.0 mL.min-1,检测波长为272 nm,以对乙酰氨基酚为内标测定血浆中没食子酸的浓度。应用DAS 2.0软件计算药物动力学参数。结果大鼠灌胃给药后t1/2α为46.57 min,t1/2β为56.54 min,tmax为66.00 min,ρmax为3.96 mg.L-1,AUC0~t为396.5 mg.min.L-1;静脉给药后t1/2α为9.90 min,t1/2β为78.88 min,AUC0~t为461.9 mg.min.L-1。结论大鼠灌胃和静脉给予没食子酸后,其药-时过程均符合二室模型,绝对生物利用度为42.9%。     

The effect of pH on the buccal and sublingual absorption of captopril

The effect of pH on the buccal and sublingual absorption of captopril was evaluated using in vitro techniques and human studies. Partitioning of captopril into n-octanol was lowest over the pH range 5 to 8 and highest at pH values 3, 4 and 9. Using the buccal absorption technique, the partitioning of captopril (2 mg) was examined in six healthy male volunteers from buffered solutions (pH 3, 4, 5, 6, 7, 8, and 9). Lowest buccal partitioning occurred at pH 3 while maximal buccal partitioning occurred at pH 7. These data clearly indicated that the buccal absorption of captopril did not obey the classical pH/partition hypothesis suggesting that mechanisms other than passive diffusion were involved in its absorption. Captopril pharmacokinetic and pharmacodynamic parameters were determined after administration of buffered sublingual captopril (pH 7, optimal pH for absorption as determined from the buccal partitioning data) and unbuffered sublingual captopril. The study was performed in eight healthy volunteers in a randomised single-blind cross-over fashion. The t_max for captopril was found to be approximately 11 minutes earlier after buffered versus unbuffered sublingual administration and AUC_{0–30 min} increased by approximately 30% in the case of buffered captopril. Cp_max, AUC_{0–180 min} and relative bioavailability did not differ between the buffered and unbuffered administration. Pharmacodynamic parameters (BP, heart rate and plasma renin activity) did not differ significantly between buffered and unbuffered sublingual administration. The increased rate of captopril absorption after buffered sublingual administration was small and is likely to offer little therapeutic advantage over conventional sublingual formulation.     

化合物Au20大鼠体内药动学及绝对生物利用度研究

目的建立HPLC法测定大鼠血浆中化合物Au20的浓度,研究其在大鼠体内的药动学及绝对生物利用度。方法双周期自身交叉设计,SD大鼠静注给药和灌胃给药化合物Au20,剂量分别为4.0和40.0 mg/kg,给药后不同时间点取血,HPLC法测定血浆中化合物Au20的浓度,用DAS 2.0软件计算其药动学参数。结果血浆中化合物Au20在7.8～1 000 ng/mL浓度范围内线性关系良好(r=0.999 9),提取回收率75.91%～89.06%,日内和日间RSD均小于5%。静脉注射给药的药-时曲线符合三室模型。经剂量校正,口服给药的绝对生物利用度为(4.08±1.85)%。结论化合物Au20口服给药的绝对生物利用度低。     

The absolute bioavailability of caffeine in man

Summary The absolute bioavailability of orally administered caffeine was investigated in 10 healthy adult male volunteers, aged 18.8 to 30.0 years. The subjects were administered a 5 mg/kg dose of caffeine as either an aqueous oral solution or an intravenous infusion, on separate occasions about 1 week apart, in a randomized crossover fashion. Plasma samples were collected over the 24-h period following each dose and assayed for their caffeine content using a high-performance liquid chromatographic technique. The oral absorption was very rapid, reaching a peak (T_p) plasma concentration after 29.8±8.1 min (mean±SEM). In addition, the variation in the maximum plasma concentration (C_max) was low, 10.0±1.0 µg/ml. The absolute bioavailability was assessed by comparing the areas under the plasma concentration vs. time curves for the intravenous and oral doses of caffeine. The rapid absorption resulted in essentially complete bioavailability of the oral caffeine, F(%)=108.3±3.6%. The caffeine plasma half-lives varied from 2.7 to 9.9 h, indicating substantial inter-subject variability in its elimination.     

Pharmacokinetics of a new sublingual formulation of temazepam

Summary The pharmacokinetics of a new 10 mg sublingual tablet formulation of temazepam and those of a currently marketed 10 mg oral capsule formulation were evaluated in a group of ten healthy volunteers.No significant differences were observed between the two formulations with respect to any of the pharmacokinetic parameters assessed. Lethargy and somnolence were reported on both capsule and tablet by several subjects at a time which corresponded with the maximum concentration of drug in plasma.The data indicate that the sublingual tablet and orally administered capsule have a similar pharmacokinetic and pharmacodynamic profile.Normison (Wyeth)     

姜黄素在大鼠体内药代动力学和生物利用度研究

目的研究姜黄素不同给药途径在大鼠体内的药代动力学和绝对生物利用度。方法建立大鼠血浆中姜黄素的HPLC检测方法。考察大鼠分别经灌胃ig(200 mg·kg-1)、ip腹腔注射(20 mg·kg-1)、舌下静脉iv(10 mg·kg-1)给予姜黄素后血药浓度变化。用DAS2.0软件计算药动学参数,根据腹腔注射、灌胃和静脉给药药-时曲线下面积AUC(0-∞)和给药剂量,计算腹腔注射和口服姜黄素的绝对生物利用度。结果姜黄素浓度在0.05～6.00 mg·L-1范围内线性关系良好(r=0.9998);定量下限为0.05 mg·L-1;低(0.10 mg·L-1)、中(1.00 mg·L-1)、高(4.00 mg·L-1)3个浓度的回收率分别为(99.29±5.40)%、(104.21±4.72)%和(99.83±1.97)%;日内RSD分别为4.49%、3.90%和1.72%,日间RSD分别为4.61%、4.27%和2.00%。大鼠经灌胃、腹腔注射和静脉注射姜黄素后,姜黄素在大鼠体内的代谢过程均符合二室模型,消除半衰期分别为(159.28±18.12)、(90.79±11.55)和(11.96±2.64)min;AUC(0-∞)分别为(86.36±12.90)、(73.39±8.72)、(104.62±11.89)mg.min.L-1。按剂量折算,姜黄素经腹腔注射给药的绝对生物利用度为35.07%,灌胃给药的绝对生物利用度为4.13%。结论姜黄素经不同途径给药在大鼠体内的药代动力学过程相似,腹腔注射给药的绝对生物利用度较高,口服生物利用度低。     

Antiarrhythmic and electrophysiologic effects of sublingual ibutilide fumarate

Ibutilide fumarate is a class III antiarrhythmic agent in phase III clinical trials. Due to rapid hepatic metabolism, ibutilide has a low oral bioavailability (< 10%). To assess alternate routes of administration, we performed repeated studies of the electrophysiologic effects of sublingual ibutilide (0.03, 0.1, and 0.3 mg/kg; 0.07, 0.2, and 0.7 m?mol/kg) in pentobarbital anesthetized dogs. Peak significant increases in QTc interval, ventricular effective refractory period (VERP), and right ventricular monophasic action potential duration (MAPD90) were achieved 30 min following 0.1 or 0.3 mg/kg (0.2 and 0.7 m?mol/kg) ibutilide and were coincident with peak plasma ibutilide levels. The duration of significant effects ranged from 2 to 5 h. Peak effects were: QTc + 121 msec, MAPD90 + 71 msec, and VERP + 53 msec. The 0.3 mg/kg (0.7 m?mol) dose significantly decreased heart rate 10 min post dosage through 5 h. The 0.03 mg/kg (0.07 m?mol) dose increased MAPD90 at 1 to 2 h but was otherwise ineffective. The plasma half life of ibutilide was 2.8 h, with a 72% bioavailability relative to an equivalent intravenous dose. Based on the electrophysiologic results, we chose to test the 0.1 mg/kg (0.2 m?mol) sublingual ibutilide dose for termination of sustained atrial flutter in anesthetized dogs with y-shaped right atrial incisions. The administration of 0.1 mg/kg (0.2 m?mol) sublingual ibutilide during sustained atrial flutter resulted in termination of atrial flutter in all cases (n = 4) after a mean time interval of 11.4 ± 0.8 min. Termination of atrial flutter was associated with ibutilide plasma levels of 19.6 ± 6.3 ng/ml, and 30 and 18 msec increases in atrial and ventricular effective refractory periods. Atrial flutter could be reinduced in 2 dogs, on at 3 h and one at 4 h post ibutilide administration. The ability to reinduce atrial flutter was associated with a reduction in ibutilide plasma levels to 2.3 ± 0.7 ng/ml. We conclude that sublingual ibutilide is rapidly absorbed and produces significant electrophysiologic and antiarrhythmic effects, and is a potential alternative to intravenous and oral therapy. ©1995 Wiley-Liss, Inc.     

青霉素V钾胶囊与片剂的药物动力学及相对生物利用度比较

目的比较青霉素V钾胶囊与片剂的药物动力学及相对生物利用度.方法以微生物法测定10名健康受试者单次空腹po青霉素V钾胶囊和片剂500mg后血、尿药浓度.结果po青霉素V钾胶囊和片剂后的体内过程符合二室模型.其平均cniax分别为(8.22±1.21)和(7.71±1.09)mg/L,tniax为(0.55±0.11)和(0.58±0.17)h,T1/2ka为(0.21±0.09)和(0.20±0.06)h,T1/2β为(0.81±0.21)和(0.72±0.08)h,AUC为(9.51±1.06)和(9.50±1.82)h@mg/L,24h累积尿排出率分别为给药量的(35.33±7.45)%和(37.80±5.45)%.青霉素V钾胶囊与片剂的药物动力学参数间差异无统计学意义(P＞0.05).结论青霉素V钾胶囊的相对生物利用度为(101.44士9.59)%,与片剂具生物等效性.     

硫酸沙丁胺醇控释小丸胶囊的人体相对生物利用度研究

目的：研究硫酸沙丁胺醇控释小丸胶囊和进口控释片及普通片在健康志愿者体内单剂量和多剂量给药后的药代动力学和生物利用度。方法：８名健康男性志愿者自身随机交叉先后ｐｏ ８ｍｇ受试硫酸沙丁胺醇控释小丸胶囊、沙丁胺醇控释片（Ｖｏｌｍａｘ）或沙丁胺醇普通片（Ｖｅｎｔｏｌｉｎ）,观察其药代动力学和相对生物利用度。另２０名受试者自身随机交叉ｐｏ受试胶囊（８ｍｇｍ,ｂｉｄ）和Ｖｏｌｍａｘ（８ｍｇ,ｂｉｂ）,连服５ｄ     

Pharmacokinetics and bioavailability of a sustained-release diltiazem formulation (Mono-Tildiem LP 300 mg) after repeated administration in healthy volunteers

The usual dosage regimen of diltiazem (Tildiem) is 60 mg 3–4 times a day. A sustained-release formulation has been developed (Mono-Tildiem LP 300 mg) in order to allow a single daily administration. Two repeated dosing studies were performed in healthy volunteers. The absolute bioavailability of sustained-release diltiazem LP 300 mg was investigated using concomitant i.v. administration of ¹³C-labelled drug: absolute bioavailability of the once a day formulation was 35%. The second study compared sustained-release diltiazem LP 300 mg with the standard formulation of diltiazem. The results showed that the diltiazem plasma concentrations obtained after the LP formulation remained stable between 2 and 14 h after administration and were compatible with a once a day administration. Relative bioavailability of sustained-release diltiazem LP 300 mg was 79.3% compared with diltiazem. Therefore, a unitary dose of sustained-release diltiazem LP 300 mg was chosen as the dose equivalent to the daily dose administered with the standard diltiazem formulation.     

Yohimbine bioavailability in humans

Summary Pharmacokinetic profiles were determined in seven healthy young male subjects following single oral and intravenous doses of 10 mg of yohimbine hydrochloride.The drug was rapidly eliminated (t_1/2 0.58 h orally and t_1/2 0.68 h intravenously). Following intravenous administration the data fit a two-compartment pharmacokinetic model, with a very rapid distribution phase (t_1/2a was approximately 6 min). Both the oral and the intravenous yohimbine clearance values were high but oral clearance values were much higher (mean 9.77 ml·min^–1·kg^–1 intravenous versus 55.9 ml·min^–1·kg^–1 oral). The oral bioavailability showed great variability, ranging from 7% to 87% (mean value was 33%).The imcomplete oral bioavailability of yohimbine may reflect either incomplete absorption from the gastrointestinal tract or an hepatic first pass effect. Although yohimbine is rapidly absorbed when given orally, the bioavailability is quite variable and considerable individualization of dosing may be necessary when the drug is used orally for clinical indications.Supported in part by NIH grant # MOIRR 0042     

The pharmacokinetics and pharmacodynamics of sublingual and oral alprazolam in the post-prandial state

Summary We gave 12 healthy male volunteers 1 mg of alprazolam or placebo on three occasions after a standard breakfast in a double-blind, randomized, single-dose, three-way crossover study.The three trials were: (a) oral alprazolam and sublingual placebo; (b) oral placebo and sublingual alprazolam; (c) placebo by both routes.Plasma alprazolam concentrations during 24 h after each dose were measured by electron-capture gas-liquid chromatography.Peak plasma concentrations were reached later after sublingual than oral dosage (2.8 vs 1.8 h, P<0.01). Other kinetic variables were not significantly different: peak plasma concentration, 11.3 vs 12.0 ng·ml^–1; elimination half-life, 12.5 vs 11.7 h; and total area under the plasma concentration versus time curve, 197 vs 186 h·ng·ml^–1.Pharmacodynamic measures showed that sublingual and oral alprazolam both produced sedation, fatigue, impaired digit symbol substitution, slowing of reaction time, and impairment of the acquisition and recall of information. These changes were initially observed at 0.5 h after dosage and lasted up to 8 h.In general the two routes were significantly different from placebo but not from each other.     

The comparative bioavailability of carbamazepine in 100 mg and 200 mg tablets

1. The bioavailabilities of carbamazepine in 100 mg and 200 mg tablets have been compared in a cross-over study of six subjects after two 600 mg doses of the drug, the different preparations being taken at 3 week intervals. 2. Areas under the plasma level curves, absorption rate constants and times to achieve peak plasma levels showed little difference between the two preparations. These findings suggest similar rates and extents of bioavailability of carbamazepine in the two preparations. 3. Calculated mean absorption and elimination parameters for carbamazepine were as follows: k_abδ= 0.1081 h^-1, (s.d. = 0.0289); T_max= 23.39 h, (s.d. = 8.66); K: = 0.0191 h^-1, (s.d. = 0.0033); V_D= 0.989 1/kg, (s.d. = 0.159); and clearance = 0.0185 1/kgh, (s.d. = 0.0015).