Pharmacokinetics of Intravenous Metronidazole in Man

Abstract: Metronidazole (500 mg) was infused over 20 min. to five patients. At the end of the infusion blood samples were drawn at brief intervals. After subsequent metronidazole analysis the curve plotted for the elimination of the drug showed a bi-exponential profile. Mean peak serum concentrations reached 15 μg per ml. At the end of the distribution phase, which was 20 to 30 min. after the infusion, the concentration had fallen to 10 μg per ml. A two-compartment model was used to calculate the kinetic parameters. The elimination half-life ranged from 4.7 to 15.8 hours, the total clearance from 43 to 193 ml per min., and the peripheral distribution volume from 41.5 to 79.1 1. The areas under the serum level curves exhibited a four-fold variation, due to differences in either metabolism or elimination rate.     

Pharmacokinetics of 2,6-cis-Diphenylhexamethylcyclotetrasiloxane in Man

Abstract: 2,6-cis-Diphenylhexamethylcyclotetrasiloxane was given to seven patients with prostatic cancer in stage IV of the disease in a single oral dose of 100 mg dissolved in soybean oil in soft gelatin capsules. Serum concentrations were determined by a gas chromatographic — mass fragmentographic method. Maximum serum levels of 1.1—5.0 mg/l were obtained after an average of 6 hours (range 4—7.5 hours). The biological half life varied between 14—23 hours, average being 18 hours. Serum concentration vs time data fitted fairly well to a pharmacokinetic two compartment open model, assuming first order absorption. The model parameters predicted steady state serum levels obtained up to 83 days of medication with fairly accurate precision.     

The Pharmacokinetics of Carbamazepine in Plasma and Saliva of Man

Abstract The excretion of carbamazepine in the saliva of six normal adults after receiving a single oral dose of 400 mg carbamazepine is described. There was a good correlation between carbamazepine concentrations in the plasma and saliva (r = 0.94, P < 0.001). This indicates that the concentrations of carbamazepine in the saliva can be used to monitor carbamazepine therapy. The half-life of carbamazepine in the plasma was not significantly different from the half-life in the saliva. Thus areas under concentration-time curves, apparent volumes of distribution (V_d) and the total body clearances were significantly dependent (P < 0.001) upon the distribution of carbamazepine between plasma and saliva. Calculated from saliva concentrations, 75 % of the total carbamazepine plasma concentration is bound to protein while 25 % is unbound in diffusional equilibrium with saliva. These figures are consistent with data in the literature.     

The Pharmacokinetics of Cyclophosphamide in Man Following Treatment with Methotrexate

Abstract The metabolism of cyclophosphamide was determined before and following treatment with methotrexate. After 9 days treatment to 7 patients with methotrexate 7.5 mg/day by mouth the rate of bio-transformation of cyclophosphamide was decreased in 2 cases, increased in 1 case and unchanged in 5 cases. After the intravenous injection of 40 mg methotrexate to 2 subjects the biotransformation of cyclophosphamide is immediately inhibited. It is argued that the inconsistency of the results after prolonged treatment with methotrexate may be due to individual variations with regard to sensitivity of the drug metabolizing enzymes to methotrexate, whereas the acute effect is probably due to an inhibition of the action of the enzymes.     

The Influence of Liposomal Encapsulation on Sodium Cromoglycate Pharmacokinetics in Man

The pharmacokinetics of pulmonary-administered sodium cromoglycate (SCG) has been studied in five healthy volunteers. SCG, 20 mg, was inhaled as a solution and encapsulated in dipalmitoyl phosphatidylcholine/cholesterol (1:1) liposomes. Liposomal SCG produced detectable drug levels in plasma from four volunteers taken 24 and 25 hr after inhalation. Inhaled SCG solution, although producing peak plasma levels more than sevenfold greater than liposomal drug, was not detectable in 24-hr samples from any volunteer. The decline in plasma levels following inhalation of liposomal SCG (reflecting the absorption phase) was best described by a biexponential equation. The two absorption rate constants differed by more than an order of magnitude. The rapid absorption phase was probably due to free or surface-adsorbed SCG in the liposomal formulation, since the absorption rate constant for this phase did not differ significantly from the absorption rate constant for SCG in solution. The phase of slow drug absorption may then be attributed to absorption of drug released from vesicles. The data indicate that encapsulation of SCG prior to pulmonary administration prolonged drug retention within the lungs and altered its pharmacokinetics.     

Bioavailability and Pharmacokinetics in Man of Orally Administered Theophylline

Abstract The pharmacokinetics of theophylline after both intravenous and oral administration was investigated in six hospitalized patients with normal renal, hepatic and pulmonary functions. A rather wide range of biological half-lives from about 3–16 hours and plasma clearance values of about 16.5–115 ml kg^-1 hr^-1 were found in the investigated patients, who were from 31 to 73 years of age. The apparent volumes of distribution during the eliminatory β-phase (V_dβ) were within the range 0.394–0.616 1 kg^-1 with a mean value of 0.484 1 kg^-1 ±0.082 S.D., as determined from the intravenous data, and in excellent agreement with the value obtained from the peroral data. Except in one case theophylline exhibited two compartment characteristics after intravenous administration, while the oral data in only one patient showed this pharmacokinetic configuration and had to be analysed according to one-compartment characteristics in the other five subjects. In the oral experiments absorption rate constants of from about 0.57 to 2.17 hr^-1 were found for the administered microparticulate theohylline tablet preparation, Nuelin® from Riker Laboratories. A wide range of lag-times from 0 to 1.32 hours were also demonstrated in the experiments. The systemic availability of theophylline in this preparation varied from 82.8 to 103% as determined on basis of the ratios of areas under the oral and intravenous serum concentration curves. It is conclusively stated that therapeutic plasma concentrations of theophylline probably may be maintained and controlled efficiently with the investigated oral theophylline preparation. Because of the interindividual variability in the biological half-life of the compound monitoring of the serum theophylline concentration is generally advised in order to avoid toxic side effects, in particular in relation to the initial establishment of a therapeutic serum concentration level in the individual subjects to be treated.     

Pharmacokinetics of Intravenously Administered L-5-Hydroxytryptophan in Man

Abstract The pharmacokinetics of 5-hydroxytryptophan were investigated in relation to intravenous administration of single doses of the amino acid (0.2 mg/kg b.wt.) to five patients pretreated for one week with carbidopa, an L-aromatic amino acid decarboxylase inhibitor. The plasma concentration/time lapse of 5-hydroxytryptophan exhibited bi-exponential disposition characteristics and the data obtained could be closely fitted to an open two compartment pharmacokinetic model with elimination taking place from the central compartment. The apparent composite 1. order rate constants α and β were 1.433 hr^-1 ± 0.177 S.D. and 0.113 hi^-1 ± 0.012 hr^-1 S.D., respectively. The biological half-life of 5-hydroxytryptophan under the experimental conditions was thus about 6 hours. The apparent volume of the central compartment, V_c, was found to be 0.336 1 kg^-1 ± 0.059 S.D. and the plasma clearance 0.105 1 hr^-1 kg^-1 ± 0.015 S.D. The derived pharmacokinetic constants were used for doses regimen calculations and predetermination of the plasma concentration/time lapse, during continuous intravenous infusion therapy. Measured plasma concentrations of 5-hydroxytryptophan during infusion deviated by less than 10 per cent from the predicted values. However, the infusions had to be stopped in four of the experiments because the patients became nauseated and vomited after total doses of only 36-128 mg.     

The Metabolism of Rimiterol Hydrobromide at Different Intravenous Dose Levels in the Rat

1. The metabolism of the β₂-adrenergic agent rimiterol in the rat has been studied at intravenous dose levels of 10 μg/kg, 1.0?mg/kg and 10.0?mg/kg.

2. The plasma half-lives of ¹⁴C-labelled material were 60?min at the two lower dose levels and 31?min at the highest dose level.

3. At the lower doses 3-O-methylrimiterol and 3-O-methylrimiterol glucu-ronide accounted for 31% of the urinary ¹⁴C excretion. At the highest dose no 3-O-methylrimiterol was excreted, there was a reduction in the urinary excretion of sulphates of rimiterol, and an increased excretion of unchanged rimiterol.

4. At the highest dose level there was a delay in uptake of ¹⁴C-labelled material into the liver which was attributed to the α-adrenergic actions of the drug causing splanchnic shut down.

5. These dose-related differences in rimiterol metabolism emphasize the need for conducting metabolic studies at several dose levels.     

利多卡因及其代谢物MEGX的人体药代动力学研究

测定了8名健康志愿和4名肝硬化患给药前及静脉注射利多卡因（1mg/kg)后3,6,10,15,30,45,60,90,120,300min利多卡因及其主要代谢物MEGX的血药浓度。通过对利多卡因和MEGX药动学模型的分析,发现肝硬化病人与正常人的MEGX药动力学参数有显差异。提示60min时的MEGX血药浓度测定,不仅可作为一种简便、无创伤性的定量肝脏功能测试的手段,也适用于药物相互作用及个体化治疗药物监测的研究。     

利多卡因及其代谢物MEGX的人体药代动力学研究

测定了8名健康志愿者和4名肝硬化患者给药前及静脉注射利多卡因(1 mg/kg)后3,6,l 0,15,30,45,60,90,120,300 min利多卡因及其主要代谢物MEGX的血药浓度.通过对利多卡因和MEGX药动学模型的分析,发现肝硬化病人与正常人的MEGX药动学参数有显著差异.提示60 min时的MEGX血药浓度测定,不仅可作为一种简便、无创伤性的定量肝脏功能测试的手段,也适用于药物相互作用及个体化治疗药物临测的研究.     

Biopharmaceutics: Drug Metabolism and Pharmacokinetics: Circadian Variations in the Pharmacokinetics of Pentoxifylline in Man

Optimization of therapy by chronopharmacology requires knowledge of rhythmic manifestations of disease activity and chronopharmacokinetic data of the drugs prescribed. Rhythmic functioning of the cardiovascular system in healthy and diseased subjects is manifested as circadian rhythms in blood pressure, cardiac output, heart rate, etc. The disposition of several cardiovascular drugs in man has been reported to be time-dependent. This study reports the effect of time of administration on the disposition of pentoxifylline. Twelve healthy volunteers were treated with 400 mg pentoxifylline orally at 0100, 0700, 1300 and 1900 h in a randomized crossover Latin-square design with a wash-out period of one week. Serum samples were analysed for unchanged pentoxifylline by HPLC. Pharmacokinetic parameters were calculated using a model-independent method. The mean values of various pharmacokinetic parameters after drug treatment at these times were, respectively: maximum plasma concentration (C_max) 485 ± 174, 646 ± 175, 735 ± 271 and 781±217 ng mL^?1; time to reach the maximum plasma concentration (T_max) 1.90±0.39, 1.66±0.4, 1.31 ± 0.41 and 1.32 ± 0.44 h, mean residence time (MRT) 3.8 ± 0.8, 2.9 ± 0.5, 2.9 ± 0.4 and 2.7 ± 0.3 h, elimination half-life (t1/2) 1.93 ± 0.86, 1.23 ± 0.3, 1.39 ± 0.3 and 1.23 ± 0.18 h and volume of distribution at steady state (Vd_ss/f) 11991 ± 4862, 8823 ± 3484, 8275 ± 2357 and 7063 ± 1950 mL kg^?1. The mean C_max value was significantly (P < 0.05) lower after drug administration at 0100 h than after other time-points whereas mean T_max, MRT, Vd_ss/f and t1/2 values were significantly (P < 0.05) higher. These variations might be because of time-dependent changes in absorption and biliary excretion of pentoxifylline and should be borne in mind when designing sustained action dosage forms for the drug.     

Dose-Dependent Pharmacokinetics of the Aldose Reductase Inhibitor Imirestat in Man

The pharmacokinetics of imirestat were studied in healthy volunteers following single and multiple oral doses. After single doses of 20 to 50 mg, imirestat plasma concentrations declined with an apparent elimination half-life of 50 to 70 hr over the 168 hr in which levels were measured. However, with lower doses (2 to 10 mg), an initial rapid decline in drug concentration was followed by a very slow terminal elimination phase with plasma concentrations decreasing little over the 1 week of sampling. This resulted in a decrease in apparent t 1/2 with increasing dose, from 272 +/- 138 hr at 2 mg to 66 +/- 30 hr at 50 mg. During once-daily dosing of 2 to 20 mg/day for 4 weeks, mean steady-state imirestat concentration appeared to be dose proportional, although the time required to achieve steady state decreased with increasing dose. The mean effective half-life for accumulation ranged from 54 to 98 hr, suggesting that the very slow elimination of drug at low concentrations did not produce disproportionate accumulation of drug at these doses. Mean oral clearance was independent of dose, ranging from 30 to 45 ml/min. At the 2-, 5-, and 20-mg doses, one subject in each group had steady-state concentrations two- to fourfold greater than any of the other five subjects at the same dose, although the reason for this was not apparent from these data. The overall kinetic profile of these data was suggestive of dose-dependent pharmacokinetics resulting from nonlinear tissue binding of imirestat.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of Alcoholic Beverages on the Pharmacokinetics of Doxycycline in Man

Abstract: In a randomized cross-over trial on six healthy medical students, alcohol (lg/kg) ingested as whisky did not modify significantly the absorption of 200 mg of doxycycline (DC) given in two tablets. Cheap red wine with a clear taste of acetic acid postponed the absorption of DC for 2–3 hours without affecting its 24-hour AUC or urinary excretion significantly. Another similar trial with other wines on 8 healthy students suggested that good regular wines do not retard DC absorption irrespective of their tannic acid content. However, acetic acid may postpone DC absorption by possibly slowing the rate of gastric emptying.     

Pharmacokinetics of Methylergometrine (Methylergonovine) in the Rabbit and Man

Abstract: Methylergometrine concentrations in human and rabbit plasma were determined by a new radioimmunoassay after a single intravenous injection (0.2 mg in man and 0.05, 0.1 and 0.2 mg/kg in rabbits). Both in man and in the rabbit methylergometrine disappeared quickly from the plasma with a mean T_1/2β of 1.8 and 1.2–1.7 min. respectively. Similarly, the T_1/2/α-values were 32.1 and 27.3–93.2 min. The mean maximal response in the rabbit uterus in situ after 0.05, 0.1 and 0.2 mg/kg intravenously dose was found at 40 sec, 26 sec, and 26 sec. after the drug administration, respectively, and the dose response curve was quite steep. A significant correlation was found between the dose and response.     

阿斯匹林肠溶缓释胶囊的人体药代动力学及生物利用度研究

本文报道口服阿斯匹林肠溶缓释胶囊及肠溶片后体内水杨酸盐的高效液相色谱测定法及正常人药代动力学和生物利用度研究的结果。12名健康志愿者，随机分为两组，分别交叉口服阿斯匹林肠溶缓释胶囊和肠溶片各600mg。阿斯匹林在体内迅速转化为活性代谢产物水杨酸，测定口服给药后不同时间血中水杨酸的浓度，使用3P87实用药代动力学程序对药一时曲线进行处理，结果表明，水杨酸在体内的代谢过程符合一室模型。单剂空腹口服阿斯匹林肠溶缓释胶囊和肠溶片后，体内水杨酸的平均峰浓度为35．52±8．28mg／L和30．32±8．96mg／L；平均达峰时间为5．70±1．25h和7．40±2．17h开均药-时曲线下面积为328.4±92．2mg／（Lh）和316．0±70．95mg／（L·h)）;消除半衰期为3．11±1．25h和3．84±1．72h；吸收迟滞时间为2．33±0．65h和3．35±1．16h。肠溶缓释胶囊的达峰时间明显短于肠溶片。缓释胶囊对片剂的相对生物利用度为103．9％。     

Paroxetine: Pharmacokinetics,Tolerance and Depletion of Blood 5-HT in Man

Abstract The tolerance of paroxetine (FG 7051). as well as its pharmacokinetics and reduction of 5-HT in blood, has been investigated in man. Three normal, healthy volunteers were administered the single doses 10, 25. 50, and 75 mg orally, and three volunteers received 10. 25, and 50 mg per day for seven or fourteen days. No toxic effect on blood. kidney, liver. heart or general condition was found by chemical and physical examinations. The pharmacokinetic studies revealed a dose dependent systemic availability, a rather slow elimination (tl,2 = approximately 16 hrs), a good fit to a one compartment open model, and an almost complete metabolism of the substance. 25 mg paroxetine per day gave a maximal reduction of 5-HT in the blood within 2-3 weeks (to approximately 0.03 pg/nil). The 5-HT levels returned to the basic levels during a three to four weeks drug-free period.     

Bioavailability and Related Pharmacokinetics in Man of Orally Administered L-5-Hydroxytryptophan in Steady State

Abstract The bioavailability of orally administered L-5-hydroxytryptophan in steady state was investigated at four increasing multiple dose levels in five patients suffering from various myoclonic disorders. An L-aromatic amino acid decarboxylase inhibitor was co-administered in all the experiments. The disposition pharmacokinetics of the amino acid had been established in the same patients in preceding intravenous single dose experiments. The finding of a direct proportionality between the size of the oral dose level of L-5-hydroxytryptophan and the corresponding areas under the plasma concentration curves within a dosage interval at steady state strongly indicates dose independent, linear pharmacokinetics of the compound. The systemic availability of L-5-hydroxytryptophan exhibited an interindividual range of 47–84%, with a mean value of 69.2% ±4.7 S.E.M. The absorption took place at a rather slow rate as judged from times of 1.8 to 3.3 hours elapsing from administration of the compound until occurance of the maximum measured plasma concentrations. Transitory nausea and vomiting were only recognized in few instances during the gradual building up of increasing steady state levels of L-5-hydroxytryptophan in the patients, and the importance of a slow initiation of therapeutical treatment with the amino acid is emphasized.