Pharmacokinetics of sustained and immediate release formulations of indapamide after single and repeated oral administration in healthy volunteers

The pharmacokinetics of a 2.5 mg immediate release (IR) formulation of indapamide was compared to a 1.5 mg sustained release (SR) formulation of indapamide after single and repeated oral administration dose using double blind randomised cross-over studies. In the first study, 12 subjects received a single dose of each treatment: IR fasted, SR fasted or with food. In the second study one tablet of either formulation was administered daily for one week at breakfast. In each study, blood samples were collected pre dose (Cmin) and up to 120 h after the last dose. Urine was collected over the dosing interval (24 h). Following a single oral administration the SR formulation had a lower dose-normalised Cmax compared to the IR formulation (17.6 +/- 6.3 vs. 39.3 +/- 11.0 ng x mL(-1), respectively), a much longer t(max) (12.3 +/- 0.4 vs. 0.8 +/- 0.3 h) and a greater t75 (15.3 +/- 6.1 vs. 1.8 +/- 1.4 h) but there were no differences in dose-normalised AUC (559 +/- 125 and 564 +/- 146 ng x h x mL(-1)) nor in t(1/2z) values (14.8 +/- 2.8 vs. 18.4 +/- 13.4 h). The SR formulation clearly demonstrated sustained release characteristics as compared to the IR formulation. Food co-administration had no effect on dose-normalised AUC for the SR formulation. After repeated administration, steady-state was achieved by day 5. The absorption rate of the SR formulation was lower and the 24 h peak-to-trough fluctuation was 4-fold lower compared to the IR formulation. After dose correction there wasno change in AUC, (726 +/- 207 and 690 +/- 183 ng x mL(-1) x h for SR and IR, respectively). The elimination parameters (t(1,2z), Ae(tau), and CLr) remained unchanged. The SR formulation showed sustained release of indapamide with a reduction in peak concentration, while steady-state level was not affected by formulations. The two formulations have the same bioavailability.     

Pharmacokinetics of glafenine and glafenic acid in patients with cirrhosis, compared to healthy volunteers

Pharmacokinetic parameters were evaluated in 12 patients with alcoholic cirrhosis and 12 healthy volunteers after a single 400 mg oral dose of glafenine. Glafenine (G) and its major active metabolite glafenic acid (GA) were measured at regular intervals using a specific high performance liquid chromatographic method. Glafenine absorption was significantly delayed in cirrhotic patients (CP) (Tmax = 2.8 +/- 1.3 hvs 1.5 +/- 0.4 h, p less than 0.01) and was dramatically reduced in 3 patients. The large hepatic 'first pass' effect observed in healthy volunteers was markedly reduced in CP (ratio Cmax GA/Cmax G = 3.6 +/- 2.9 vs 18.9 +/- 9.8, p less than 0.001; ratio areas under the curves AUC GA/AUC G = 2.3 +/- 2.3 vs 18.2 +/- 11.2, p less than 0.001). The elimination half-life of G was prolonged in the CP (13.0 +/- 13.1 h vs 1.5 +/- 0.5 h, p less than 0.01). In CP, GA elimination half-life was increased (12.0 +/- 13.4 h vs 4.3 +/- 1.3 h, NS) but the difference did not reach statistical significance because of large variability. The significant rise of G plasma concentrations (Cmax = 2.2 +/- 2.1 mg/L vs 0.7 +/- 0.2 mg/L, p less than 0.05) and its longer half-life would lead to an accumulation if the usual dosage regimen was prescribed for CP and could result in nephrotoxicity. On the other hand, lower dosage would be ineffective because only GA is active and nephrotoxic. Hence, G should be given with great caution to CP.     

阿莫西林分散片与阿莫西林片的药代动力学比较研究

目的建立测定人血浆中阿莫西林浓度的RP-HPLC法,比较阿莫西林分散片与阿莫西林普通片在健康人体内药代动力学差异。方法选择12名男性健康志愿者分为2组,分别单剂量口服阿莫西林分散片与阿莫西林普通片各500 mg,采用高效液相色谱法检测阿莫西林的血药浓度。结果阿莫西林分散片与阿莫西林普通片主要药代动力学参数C_(max)分别为(742.8±68.4)μg/L和(676.7±57.2)μg/L,t_(max)分别为(2.7±0.3)h和(3 4±0.6)h,t_(1/2)分别为(4.9±1.5)h和(5.9±1.8)h,AUC_0~∞分别为(6 417.3±167.5)μg/(h·L)和(4 704.8±117.9)μg/(h·L),AUC_0~1分别为为(4 927.4±119.7)μg/(h·L)和(3436.5±103.5)μg/(h·L)。结论阿莫西林分散片t_(max)、t_(1/2)小于普通片,AUC_0~t、AUC_0~∞、C_(max)高于普通片,说明阿莫西林分散片具有一定的速释优点,明显优于普通片。     

单剂口服吉米沙星临床药动学研究

目的 研究单剂口服吉米沙星在中国健康志愿者中的药动学特性,为制订用于中国人的安全有效的给药方案提供依据.方法 12名受试者随机、开放、3交叉单剂空腹口服吉米沙星片剂160 mg、320 mg和480 mg.以高效液相色谱(HPLC)-荧光法测定血、尿样中吉米沙星药物浓度.应用Winnonlin分析软件计算药动学参数.结果 受试者单剂空腹口服吉米沙星160 mg、320 mg和480 mg后体内过程均符合非房室模型,平均血清Cmax分别为(0.70±0.19)mg/L、(1.40±0.32)mg/L和(1.84±0.35)mg/L;Tmax中位数分别为1(0.5,2)h、1(0.5,2)h和1.25(1,2)h;平均t1/2分别为(7.06±1.22) h、(7.02±0.94) h和(7.28±0.81) h;平均AUC0-24 h分别为(3.86±0.56) mg·h /L、(7.61±0.93) mg·h /L和(11.47±1.68) mg·h/L;平均AUC0-∞分别为(4.01±0.57) mg·h /L、(7.71±0.92) mg·h /L和(11.62±1.72) mg·h/L;平均Vd分别为(411.45±77.88)L、(423.47±59.48)L和(439.21±55.55)L;平均CLt分别为(40.71±6.22)L/h、(42.10±5.46)L/h和(42.26±7.14)L/h;给药后48 h内平均累积尿排出率分别为(38.95±6.14)%、(37.84±6.62)%和(35.57±5.07)%.结论 中国健康受试者单次空腹口服吉米沙星160～480 mg结果显示其符合线性药动学的特性,消除半衰期长.给药量的约40%以原形药物经肾排出.     

尼扎替丁分散片与尼扎替丁普通片在健康人体内的药代动力学研究

目的比较尼扎替丁分散片与尼扎替丁普通片在健康人体内药代动力学行为。方法 12名男性健康志愿者均分为2组,分别单剂量口服尼扎替丁分散片与尼扎替丁普通片150 mg,用高效液相色谱法检测尼扎替丁的血药浓度。结果尼扎替丁分散片与尼扎替丁普通片主要药代动力学参数Cmax分别为(1614.8±106.2)μg/L和(1 311.7±89.5)μg/L,tmax分别为(1.0±0.6)h和(1.5±0.4)h,t1/2分别为(4.8±1.3)h和(5.3±1.1)h,AUC0∞分别为(4731.3±118.29)μg/(h.L)和(4518.6±108.3)μg/(h.L),AUC0t分别为(2216.7±106.9)μg/(h.L)和(2187.4±78.9)μg/(h.L)。结论尼扎替丁分散片的tmax、t1/2明显小于普通片,Cmax又明显高于普通片,说明尼扎替丁分散片具有良好的速释效果。     

Pharmacokinetics of oral ciprofloxacin, 100 mg single dose, in volunteers and elderly patients

The pharmacokinetics of ciprofloxacin following a single 100 mg oral dose were evaluated in elderly patients (mean age 74 years), laboratory staff (30-40 years) and students (less than 20 years). There were no significant differences in serum Tmax (1.2-1.3 h) or in overall serum elimination half-life (3.7-4.0 h) but Cmax in elderly patients was more than double that in young volunteers (P less than 0.005). The serum AUC value was greater both in fasting students (1.4 mg/h/l) compared with the same subjects after food (1.09: P less than 0.01) and, after food, in elderly patients (1.95) compared with students (0.81: P less than 0.005). Urinary recoveries were greater in fasting subjects and in all categories of volunteers compared with elderly patients. However, in the elderly, urinary ciprofloxacin concentrations (0-6 h mean 66 mg/l: range 17.4-200 mg/l) were more than adequate for the eradication of urinary pathogens.     

Pharmacokinetics and effect of food after oral administration of prolonged-release tablets of ropinirole hydrochloride in Japanese patients with Parkinson's disease

What is known and Objectives: Ropinirole hydrochloride, a dopamine receptor agonist with a non‐ergot alkaloid structure, is highly selective for the dopamine D₂/D₃ receptors. This study was conducted to evaluate the steady‐state pharmacokinetics, safety and efficacy after repeated oral administration of prolonged‐release tablets of ropinirole hydrochloride in the absence of L‐dopa preparations in Japanese patients with Parkinson’s disease (PD). Methods: This was a multicenter, open‐label, uncontrolled study. The total duration of participation in the study ranged from 56 to 63 weeks. In the study, the plasma concentrations of ropinirole, its major metabolite SK&F104557 (N‐depropyl ropinirole) and another metabolite SK&F89124 (ropinirole hydroxylated at the seventh position of the indole ring) were assessed. Safety based on adverse events, haematology, biochemistry, urinalysis and electrocardiography (ECG) (standard 12‐lead ECG) were evaluated, and vital signs (blood pressure/pulse rate) were measured. Efficacy based on the Japanese version of Unified Parkinson’s Disease Rating Scale (UPDRS) Parts III (motor) and II [activities of daily living (ADL)] as well as tolerability was evaluated. Results: After repeated oral administration of prolonged‐release tablets of ropinirole hydrochloride in Japanese patients with PD, ropinirole, SK&F104557 and low levels of SK&F89124 were detected in plasma. The trough concentrations of ropinirole and the two metabolites increased in proportion to the dose when ropinirole hydrochloride prolonged‐release tablets were administered at doses ranging from 2 to 16 mg/day. The plasma exposure to ropinirole and its two metabolites after intake of normal diet was comparable to that in the fasting state. The most common adverse events (10% or more) were somnolence, nausea, constipation, hallucination and nasopharyngitis. Most adverse events were mild or moderate in severity, and with no death. During the treatment period, serious adverse events were reported in five patients. Efficacy analysis (LOCF) at the final endpoint up to week 16 demonstrated a mean (SD) change from baseline in the Japanese UPDRS III (motor) and II (ADL) scores of ?11·3 (8·21) and ?3·9 (3·22), respectively, and thereafter remained at similar levels until week 52. What is new and Conclusions: After administration of prolonged‐release tablets of ropinirole hydrochloride in the absence of L‐dopa preparations in Japanese patients with PD, the plasma pharmacokinetics of ropinirole and its metabolites was linear and not affected by food. Compared with the immediate‐release (IR) tablet, the prolonged‐release tablet can be administered to Japanese patients with PD at a reduced daily dose frequency and adjusted to the maintenance dose after fewer dose changes with a smaller diurnal variation in the plasma ropinirole concentration.     

Pharmacokinetics of perindopril and its metabolites in healthy volunteers

Perindopril, an angiotensin converting enzyme (ACE) inhibitor, is converted in vivo to its active diacid metabolite, perindoprilat and to a perindoprilat glucuronide. The pharmacokinetic parameters of perindopril, perindoprilat and perindoprilat glucuronide were evaluated after single administration to healthy volunteers (N = 12) of 8 mg of perindopril tert-butylamine salt by oral route (treatment A), by intravenous route (bolus in 5 min, treatment B) and of an equimolar dose of perindoprilat (6.1 mg) by intravenous route (infusion over 2 h, treatment C). The treatments were administered as a randomised 3-way cross-over design. Plasma samples were collected up to 96 h and urines up to 120 h. Perindopril is rapidly absorbed with an oral bioavailability of 95% and is mainly eliminated by metabolic processes. The formation of perindoprilat is slow and about 20% of the available parent drug is transformed into this metabolite. Elimination profile of perindoprilat is biphasic, with a rapid renal excretion of the free fraction and a long terminal half-life of the fraction bound to ACE. Perindoprilat glucuronide is mainly obtained from perindopril by a pre-systemic first pass metabolism.     

Effect of a single oral dose of two erythromycin ethylsuccinate formulations on gastric emptying in healthy volunteers: A scintigraphic study

Summary— Macrolides are potential gastrokinetic agents. The purpose of this study was to assess the effect of a single oral dose of two erythromycin formulations on gastric emptying of the solid and liquid phases in twelve healthy volunteers and to seek a correlation between pharmacokinetic parameters and changes in gastric emptying. The gastric emptying times of liquids and solids were measured simultaneously by means of a scintigraphic technique after a single oral administration of amorphous erythromycin ethylsuccinate (500 mg), crystalline erythromycin ethylsuccinate (1000 mg) or a placebo, in a double-blind crossover study in three separate weeks. Blood samples were obtained for erythromycin assay. The two oral formulations induced a similar acceleration of gastric emptying. When compared to the placebo, both erythromycin preparations significantly shortened the gastric transit time of solids and liquids (respectively 30% and 20% on average, p < 0.01). The incidence of gastrointestinal side-effects was similar with the two erythromycin forms and the placebo. No correlation was found between the peak serum erythromycin concentrations and the solid or liquid gastric half-lives. With the amorphous formulation, the area under the plasma time-concentration curves was small and solid and liquid gastric emptying were strongly accelerated, pointing to a direct effect on the gastrointestinal smooth muscle.     

Pharmacokinetics and tolerability of gemifloxacin (SB-265805) after administration of single oral doses to healthy volunteers

Gemifloxacin (known as SB-265805 or LB-20304) is a potent, novel fluoroquinolone compound with a broad spectrum of antibacterial activity. The pharmacokinetics and tolerability of oral gemifloxacin were characterized in healthy male volunteers after a single dose of 20, 40, 80, 160, 320, 600, or 800 mg. Multiple serum and urine samples were collected and analyzed for gemifloxacin using high-performance liquid chromatography with fluorescence detection. Safety assessments included vital signs, 12-lead electrocardiogram readings, hematology, clinical chemistry, urinalysis, and adverse-experience monitoring. Gemifloxacin was rapidly absorbed after all doses. Maximum concentrations of gemifloxacin in serum (C(max)) were achieved approximately 1 h after dosing, after which concentrations in serum declined in a biexponential manner. Values of C(max) and the area under the concentration-time curve in serum from 0 h to infinity (serum AUC(0-infinity)) increased linearly with dose. Serum AUC(0-infinity) values (mean +/- standard deviation) were 0.65+/-0.01, 1.28+/-0.22, 2.54+/-0.31, 5.48+/-1.24, 9.82+/-2.70, 24.4+/-7.1, and 31.4+/-7.6 microg. h/ml following 20-, 40-, 80-, 160-, 320-, 600-, and 800-mg doses, respectively. The terminal phase elimination half-life was independent of dose, with an overall mean of 7.4+/-2.0 h. The profiles indicated that the pharmacokinetic profile is suitable for a once-daily dosing regimen. Approximately 25 to 40% of the administered dose was excreted unchanged in the urine, and renal clearance (ca. 150 ml/min) was independent of dose. There were no significant changes in clinical chemistry, hematology, or urinalysis parameters, vital signs, or 12-lead electrocardiogram readings in subjects, irrespective of dose. The results of these studies support the further investigation of once-daily administration of gemifloxacin.     

Pharmacokinetics of cinoxacin in elderly patients following repeated oral administration

Cinoxacin is an antibacterial drug belonging to the quinolone class used in the treatment of urinary tract infections due to common gram-negative pathogens. Considering the high frequency of urinary tract infections in elderly people where aging represents a physiopathological condition frequently requiring an adjustment of the dosage regimen, the pharmacokinetic behaviour of cinoxacin (500 mg/12 h) in aged patients was investigated to find out if age-dependent differences may be established. The main differences detected were a shift to 4 h of the Tmax and a partly reduced clearance in comparison with data referred to younger people. On the other hand the findings showed that no accumulation occurred. High urinary concentrations of cinoxacin, exceeding the MICs for most urinary tract pathogens were found up to the 12th hour after administration.     

Pharmacokinetics and tolerance of a new film-coated tablet of sodium fusidate administered as a single oral dose to healthy volunteers

Single oral doses of 250, 500, 750 and 1000 mg of sodium fusidate as one, two, three and four film-coated 250 mg tablets were compared in a cross over design trial with a solution dose of 500 mg in 12 healthy male volunteers. The effect of food on absorption of two-film coated tablets was also studied. Compared with the dose given as a solution, tablets gave complete oral absorption, the area under the curve (AUC) for blood concentration being virtually identical. After administration of 250, 500, 750 and 1000 mg the mean of the maximum serum concentrations (Cmax) was 11.6 +/- 1.1, 30.6 +/- 2.2, 48.1 +/- 3.0 and 65.2 +/- 4.2 mg/l, respectively, indicating a greater than expected increase in Cmax with increasing dose. This was also apparent with AUC, while there was a significant trend for beta, the terminal slope of the serum/concentration time curve, to decrease. Food significantly reduced Cmax and delayed Tmax but did not affect AUC or beta. Dosage had no effect on parameters of renal, hepatic or haemopoietic function but 25% of the volunteers complained of upper gastro-intestinal symptoms mainly at the highest dose studied.     

Pharmacokinetics of intravenous and oral pentoxifylline in healthy volunteers and in cirrhotic patients

The pharmacokinetics of pentoxifylline were investigated in six healthy volunteers and in 10 patients with alcoholic cirrhosis. After a 100 mg intravenous infusion, pentoxifylline elimination half-life was prolonged in cirrhotic patients (2.12 +/- 1.22 hours versus 0.83 +/- 0.29 hours, p less than 0.05) because of a decrease in its plasma clearance (1.44 +/- 0.46 L.hr-1.kg-1 in patients with cirrhosis versus 3.62 +/- 0.75 L.hr-1.kg-1 in volunteers, p less than 0.001). The elimination half-life of the metabolite (5-hydroxypentoxifylline) was similar to that of the parent compound. After oral administration of a 400 mg sustained-released tablet, absolute bioavailability of pentoxifylline increased in cirrhotic patients (0.71 +/- 0.24 versus 0.33 +/- 0.13, p less than 0.01). Although plasma concentrations of pentoxifylline and hydroxypentoxifylline were significantly increased in cirrhotic patients, the AUCpentoxifylline/AUChydroxypentoxifylline ratio remained unchanged in both groups after either intravenous or oral administration. These findings show that liver cirrhosis profoundly alters the pharmacokinetics of pentoxifylline. However the formation of hydroxypentoxifylline is not modified in these patients, suggesting an extrahepatic metabolism.     

Pharmacokinetics of imipenem in healthy volunteers following administration by 2 h or 0.5 h infusion

OBJECTIVES: The aim of this study was to demonstrate the t > MIC of 0.5 and 1 g of imipenem when administered by 2 h infusion every 6 h compared with 0.5 g of imipenem when administered by 0.5 h infusion every 6 h. METHODS: The study was a randomized three-way crossover study with a 30 h wash-out period in eight healthy volunteers. Each subject received imipenem in three regimens: (i) a 0.5 h infusion of 0.5 g every 6 h for three doses; (ii) a 2 h infusion of 0.5 g every 6 h for three doses; and (iii) a 2 h infusion of 1 g every 6 h for three doses. RESULTS: Following 0.5 h infusion of 0.5 g, the percentages of time above four times an MIC of 4, 2 and 1 mg/L were 21.5 +/- 2.2%, 38.6 +/- 3.5% and 57.5 +/- 4% of a 6 h interval, respectively. For the 2 h infusion of 0.5 g, the percentages of time above four times an MIC of 4, 2 and 1 mg/L were 26.9 +/- 8.5%, 48.0 +/- 3.5% and 65.4 +/- 3.2% of a 6 h interval, respectively. For the 2 h infusion of 1 g, the percentages of time above four times an MIC of 4, 2 and 1 mg/L were 51.6 +/- 5.4%, 67.8 +/- 4.5% and 87.8 +/- 5.6% of a 6 h interval, respectively. CONCLUSIONS: A 2 h infusion resulted in a greater t > MIC than those after a 0.5 h infusion and intermittent infusion may be a useful mode of administration of imipenem in tropical countries.     

Tear concentrations of levofloxacin following topical administration of a single dose of 0.5% levofloxacin ophthalmic solution in healthy volunteers

BACKGROUND: Several fluorinated carboxyquinolones are used to treat ocular infectious disease. Levofloxacin, in particular, has demonstrated activity against both gram-negative and gram-positive bacteria. OBJECTIVES: An open-label study was undertaken to assess the pharmacokinetics and ocular bioavailability of levofloxacin in human tears, and to determine the tear concentration of levofloxacin in healthy volunteers, following topical administration of a single-dose of 0.5% levofloxacin ophthalmic solution. METHODS: Volunteers received 1 drop of 0.5% levofloxacin in each eye and were assigned sequentially to 1 of 5 groups for tear sampling. Tear samples were collected on Schirmer test strips at 9 predetermined time points ranging from 5 minutes to 24 hours after administration. Six tear samples were collected at each time point (1 eye each from 6 volunteers), except the 24-hour time point, at which 12 samples were collected (both eyes of 6 volunteers). No eye had > 1 tear sample taken during the study. Levofloxacin concentrations were measured using reverse-phase high-performance liquid chromatography. RESULTS: Thirty volunteers were enrolled, with 6 assigned to each of the 5 sampling groups. At 5 minutes after administration of a single topical dose of levofloxacin, the mean tear concentration was 49.19 +/- 26.73 microg/mL. The mean peak concentration of levofloxacin in the tear film, 221.06 +/- 256.68 microg/mL, was reached at 15 minutes after administration. At 4 hours after administration, the mean tear concentration of levofloxacin was 17.04 +/- 15.13 microg/mL. At 6 hours after administration, the mean concentration of levofloxacin was 6.57 +/- 5.26 microg/mL. At 24 hours after administration, levofloxacin concentrations > 2 microg/mL were measured in 2 of 6 (33%) subjects. CONCLUSIONS: Levofloxacin concentrations in the tear fluid after a single topical dose (1 drop) reached high levels quickly and remained above the minimum inhibitory concentration for most suspected ophthalmic pathogens (< or = 2 microg/mL) for at least 6 hours in most healthy volunteers, and for up to 24 hours in some volunteers.     

Pharmacokinetics of [14C]FCE 22891, a penem antibiotic, following oral administration to healthy volunteers.

FCE 22891 is a prodrug of the penem antibiotic FCE 22101 and is suitable for oral administration. The pharmacokinetics of FCE 22891 were investigated in four healthy male volunteers following the oral administration of 500 mg of [14C]FCE 22891. Levels of radioactivity in plasma were always higher and persisted for longer than those of FCE 22101. The time to the maximum concentration of radioactivity in plasma generally coincided with that of FCE 22101. The respective values for the maximum concentrations of radioactivity in plasma were, on average, 8.57 +/- 2.95 micrograms equivalent/ml and 2.97 +/- 2.05 micrograms/ml. Over a 5-day period, mean urinary and fecal recovery of radioactivity accounted for 53.2 and 41.0% of the dose, respectively. The average amount of FCE 22101 excreted in urine and feces corresponded to 9.0 and 1.6% of the dose, respectively. The urinary recovery of the open-ring metabolite P1 and of its 5-S epimer P2 accounted for about 6.5 and 1.2% of the dose, respectively. Other chromatographic peaks corresponding to nonidentified compounds accounted for about 14.0% (polar metabolite fraction; peak P), 3.7% (less polar fraction; peak X), and 15.4% (least polar fraction) of the dose. Elimination of radioactivity and FCE 22101 in urine was rapid. Intersubject variability in the kinetics of total radioactivity in plasma was far less than that observed for FCE 22101. The results of the present study support suggestions that presystemic metabolism of FCE 22101 and/or transformation of the prodrug to compounds other than FCE 22101 are the main cause of intersubject variability in the kinetics of FCE 22101 produced in plasma following oral administration of its prodrug.     

Pharmacokinetics and safety of bromotetrandrine (BrTet, W198) after single-dose intravenous administration in healthy Chinese volunteers

Objective: To investigate the safety and pharmacokinetics of bromotetrandrine (BrTet, W198), a novel inhibitor of P‐glycoprotein (P‐gp), after single‐dose i.v. infusion in healthy Chinese volunteers. Methods: We conducted a randomized, dose‐escalating, phase I clinical study for that purpose. Thirty healthy subjects received BrTet at the doses of 10, 20 or 30 mg/m² by i.v. infusion. Plasma and urine concentrations of bromotetrandrine were determined by using a liquid chromatography–tandem mass spectrometric (LC/MS/MS) method. AUC was calculated by the trapezoidal rule extrapolation method. C_max, T_max, t_1/2α, t_1/2β, Cl and V_d were compiled from the plasma concentration–time data. Results: Bromotetrandrine was generally well tolerated at all doses. No serious or severe adverse events were found in the study. The pharmacokinetic parameters of BrTet after single i.v. infusion doses of BrTet 10, 20 and 30 mg/m² were as follows: T_max were 1·5 h in three groups, C_max were 24·79, 39·59 and 64·31 μg/L, t_1/2α were 0·37, 0·29 and 0·30 h, t_1/2β were 62·88, 56·45 and 52·20 h. AUC_0–194h were 345·83, 688·15 and 1096·28 μg h/L, Cl were 23·68, 25·69 and 25·66 L h/m², V_d were 157·73,156·96 and 140·73 L/m². In urine, the total eliminate rate of originate compound was 0·61 ± 0·19%. Conclusions: This study suggested that bromotetrandrine was well tolerated in healthy volunteers within the dose range evaluated. The pharmacokinetics parameters of bromotetrandrine indicated that the compound was rapidly distributed and accumulated in the tissues, and slowly cleared from plasma, which supported the use of BrTet for a once or twice dosing per chemotherapy cycle.     

Pharmacokinetics of 14C-radioactivity after oral intake of a single dose of 14C-labeled fampridine (4-aminopyridine) in healthy volunteers

Background: Fampridine (4-aminopyridine) is a potassium channel blocker that has been evaluated as a treatment for patients with spinal cord injury and multiple sclerosis.Objective: The purpose of this study was to determine the pharmacokinetics of a single dose of an orally administered solution of ¹⁴C-labeled fampridine in healthy volunteers.Methods: In this open-label, single-dose study conducted in an inpatient setting, healthy adult men were administered an oral solution containing 15 mg of ¹⁴C-labeled fampridine (100 μCi) in a fasted state. In addition to blood sampling for analysis of plasma ¹⁴C-radioactivity at prescribed intervals over 7 days, all urine and feces were collected for analysis of drug recovery and disposition. Urine samples were also analyzed for metabolic profiling. Plasma pharmacokinetic parameters of the ¹⁴C-radiolabeled drug were determined using standard liquid-scintillation techniques. Recovery was calculated to provide the total amount of radioactivity excreted as a proportion of the original dose. Nonhydrolyzed and hydrolyzed urine extracts were analyzed for radioactivity and metabolites using reverse-phase, isocratic high-performance liquid chromatography with spectrophotometric and radioactive detection. Tolerability was assessed through evaluation of vital signs, hematologic and other laboratory parameters, and electrocardiography.Results: The 4 white male subjects had a mean (SD) age of 21 (2) years. No clinically significant abnormalities in vital signs, clinical chemistry, hematology, urinalysis, or electrocardiography were observed either before or during the study. Peak plasma radioactivity was reached at 1 hour after dosing, with a median concentration of 72.9 ng · mL^?1. There was complete disappearance of radioactivity by 24 hours (limit of quantitation, 400 disintegrations/min per peak), and the calculated median t_1/2 was 3.14 hours. Total cumulative recovery of ¹⁴C-radioactivity was 96.36%, with only 0.51% of drug recovered in feces. On chromatography, 2 metabolites accounted for a low proportion of total urinary radioactivity (3% and 6% of total radioactivity in the interval from 0 to 4 hours after dosing; 17% and 9% in the interval from 8 to 12 hours after dosing). Three subjects reported mild and transient dizziness occurring 1 half-hour after dosing; this was considered possibly related to the study drug.Conclusion: Fampridine administered as an oral solution was rapidly absorbed and was nearly completely and rapidly eliminated as unchanged drug via urinary excretion, suggesting that it is unlikely to undergo substantial metabolic transformation.