Pharmacokinetic Study of Mitomycin C with Emphasis on the Influence of Aging

Mitomycin C (MMC) at a dose of 8 mg/m² was administered by short intravenous infusion to 14 cancer patients. All patients had normal renal, hepatic, cardiac and bone marrow functions. The plasma level of MMC, which was determined by high-performance liquid chromatography over a 24–h period after the infusion, fitted the 2-compartment model curve except for one patient. There was a significant correlation between the area under the time versus concentration curve (AUC) of MMC and the age of patients ( r = 0.558, P < 0.05). Pharmacokinetic parameters in one of the older (a 69-year-old male) patients were extremely different from those of the other 13 patients. This patient experienced severe myelosuppression, probably due to the markedly increased AUC of MMC. Our results suggest that a patient's age has a significant influence on the pharmacokinetics of MMC in patients with normal major organ functions and that in some patients, MMC pharmacokinetics may be altered, possibly due to interpatient variation in the activation or metabolic pathway of MMC.     

99Tcm-MIBI动力学变化与大鼠缺血-再灌注心肌存活的相关性研究

目的探讨用99Tcm-甲氧基异丁基异腈(MIBI)动力学变化评价心肌存活的价值.方法15只离体Krebs-Henseleit(KH)液灌注的鼠心脏,随机分成3组对照组(5只),有葡萄糖的缺血-再灌注组(IR+G组,5只),无葡萄糖的缺血-再灌注组(IR-G组,5只).用含99Tcm-MIBI(14.8MBq)的KH液灌注,观察40min的摄取和清除.用肌酸激酶(CK)分析、氯化三苯四唑(TTC)染色和透射电镜(TEM)分析研究心肌损伤程度,用放射自显影(ARG)观察99Tcm-MIBI在心肌内的分布.结果99Tcm-MIBI的摄取[每克组织百分注射剂量率(%ID/g)]在IR+G组为(7.09±0.97)%ID/g,IR-G组为(6.64±0.68)%ID/g,对照组为(11.44±1.79)%ID/g,IR-G组与IR+G组相比摄取量差异无显著性(P＞0.05),IR-G组和IR+G组与对照组相比均显著降低(P＜0.05).IR-G组99m-MIBI清除分数为(72.75±9.89)%,远高于对照组[(20.68±1.92)%]和IR+G组[(21.03±3.68)%,P均＜0.05],对照组与IR+G组的差异无显著性.99Tcm-MIBI的40min清除末滞留率在IR-G组[(1.82±0.73)%ID/g]和IR+G组[(5.61±0.89)%ID/g]远小于对照组[(9.09±1.57)%ID/g,P＜0.05],IR-G组也远小于IR+G组(P＜0.001).CK分析、TFC染色和TEM分析证明IR-G组比IR+G组有更多的心肌损伤.通过TTC染色(r=0.84,P＜0.05)和CK分析(r=-0.97,P＜0.05)确定最终99Tcm-MIBI的活度与存活心肌量高度相关,通过ARG证实99Tcm-MIBI分布于鼠心肌细胞及间质内(光镜下).结论99Tcm-MIBI的清除对代谢状态敏感,可用于评价进行性心肌损伤.     

潘库溴铵在婴幼儿、儿童和成年人的药代动力学

研究观察年龄对潘库溴铵药代动力学的影响，选择24例施择期整形外科手术的患者，根据年龄分成三组：1组为5例婴幼儿，年龄0．75－2．95岁；2组为13例儿童，年龄4－14岁；3组为6例病人，年龄16－27岁，静注潘库溴铵100ug/kg后用改良蒌光法测定其血浓度，潘库溴铵的体内过程能用二室开放模型完整描述，年龄愈小，分布容积愈大，血浆清除率愈高，潘库溴铵的血药浓度愈低，V1（中央室分布容积），V2（周边室分布容积），Vdss(稳态分布容积），C1（血浆清除率）和AUC（曲线下面积）在三相间有明显差别，1组的T1／2β和MRT明显比2，3组长，但T1／2α和K21在三组间无明显差别。     

Pharmacokinetics of Controlled Release and Immediate Release Morphine Sulphate Tablets after a Single Dose and Multiple Doses in Chinese Volunteers

健康志愿者１０名，随机交叉口服硫酸吗啡控释片（ＣＲＭＳ）３０ｍｇ（３０ｍｇ×１）和硫酸吗啡普通片（ＩＲＭＳ）２０ｍｇ（１０ｍｇ×２），分别于服药前后各时点取静脉血，用ＧＣＭＳ测定血浆中吗啡含量。以药代软件程序处理，分别求得ＣＲＭＳ和ＩＲＭＳ的Ｃｍａｘ为１９．３８±３．８０和２１．２７±６．２１ｎｇ／ｍｌ；ｔｍａｘ为２．３６±０．３７ｈ和０．５５±０．１６ｈ；ｔ１／２β为３．５３±０．８７ｈ和３．０３±０．７４ｈ，曲线下面积ＡＵＣ为１４５．１５±１７．６５和９３．０８±１６．６５ｎｇ·ｈ／ｍｌ。癌症病人多次口服硫酸吗啡至稳态，ＣＲＭＳ和ＩＲＭＳ的峰浓度分别为２７．４３±０．３３ｎｇ／ｍｌ，２２．６８±０．１６ｎｇ／ｍｌ；谷浓度分别为１９．４５±１．４４ｎｇ／ｍｌ；１８．１４±０．４９ｎｇ／ｍｌ。     

Effect of omeprazole on the anticoagulant activity and the pharmacokinetics of warfarin enantiomers in rats

The effect of the proton pump inhibitor omeprazole on the anticoagulation and the pharmacokinetics of warfarin enantiomers was studied in rats. Omeprazole given intraperitoneally in a daily dose of 0.67 mg/kg over 8 days had no significant effect on the absorption, distribution and the total serum clearance values of the S- and R-enantiomers of warfarin. Omeprazole did not affect the pre-treatment baseline blood coagulation and the in vitro rat serum protein binding of warfarin enantiomers. In vitro study with rat liver microsomes showed that omeprazole had an inhibitory effect on the hydroxylation of warfarin enantiomers. Results obtained from in vivo urinary excretion study revealed that omeprazole inhibited the formation clearance of both S- and R-form oxidative metabolites, but increased that of the overall reductive metabolites, and the renal clearance of S- and R-enantiomers, of warfarin. As a consequence, the total serum clearance values for warfarin enantiomers remained unchanged and the hypoprothrombinaemic response produced by warfarin was not affected.     

Pharmacokinetics of piperacillin and tazobactam in critically ill patients with renal failure, treated with continuous veno-venous hemofiltration (CVVH)

Objective: Kinetics of piperacillin (pip), in combination with the beta-lactamase inhibitor tazobactam (taz) have been studied in volunteers and patients in relatively stable conditions. The fixed drug preparation appeared to have ideal pharmacokinetic properties if renal function was normal or slightly impaired, but no data are available for critically ill patients in anuric renal failure. This study should provide such data. Patients, design: We studied the pharmacokinetics in nine patients with multiple organ failure, including anuric renal failure, treated with continuous veno-venous hemofiltration (CVVH). Patients received a standard schedule of 4 g pip and 0.5 g taz administered over 0.5 h intravenously, 8 hourly. During 2 consecutive days, the serum levels of both compounds were determined, and total clearance (CI_T) was calculated from serum concentrations. Results: All nine patients completed day 1, and 8 completed day 2 of the protocol. On day 1, single-dose kinetics showed considerable spread, but pip/taz serum levels followed the pattern as expected, with a pip / taz concentration ratio of 20 : 1. On day 2, however, taz serum concentrations showed a relative increase as compared to pip, resulting in a change in the serum pip/taz concentration ratio to 10 : 1 on day 2. The CI_T of pip was 2.52 ± 1.38 l/h (t ¹/₂ : 5.9 ± 2.9 h), and CI_T of taz 4.44 ± 2.28 l/h (t ¹/₂ : 8.1 ± 3.7 h). The CI_T and t ¹/₂ of pip and taz correlated highly significantly with clearance by CVVH. Despite a higher CI_T, taz has a longer half-life, because of a higher volume of distribution. Conclusion: In CVVH dependent patients, pip/taz fixed drug preparations can be used initially, but the pip dosage should be increased relative to that of taz (or interval-adjusted) to prevent cumulation of taz, as compared to the active antimicrobial agent pip. Received: 19 February 1997 Accepted: 20 May 1997     

Factors controlling the selectivity and efficiency of tumour damage in photodynamic therapy

The scope and potential of the photodynamic therapy of tumors can be enhanced through an adequate control of the factors which improve the selectivity of tumour targeting by the systemically injected photosensitizer and increase the efficiency of photosensitized tumour damage. Promising results are obtained by using hydrophobic photosensitizers which can be specifically transported and released to the tumour by serum lipoproteins, especially low-density lipoproteins. The photosensitizer molecule should possess those structural features which induce a high probability of photoactivation by 700–800 nm light, as well as a high yield of long-lived triplet state. The use of liposome-delivered Zn-phthalocyanine as a second generation phototherapeutic agent for tumours is proposed.     

Pharmacokinetics of the acetylcholinesterase oxime reactivator, HI-6, in rhesus monkeys (Macaca mulatta): effect of atropine, diazepam, and methoxyflurane anesthesia

The pharmacokinetics of the bispyridinium oxime HI-6 (CAS reg. no. 34433-31-3; 1-(((4-aminocarbonyl)pyridinio)methoxy)methyl)-2-[hydroxy i mino)methyl)- pyridinium dichloride) was investigated in rhesus monkeys (Macaca mulatta). The effects of methoxyflurane anesthesia, administration of atropine with and without diazepam were determined on the serum half-life (t1/2), clearance rate (CL), and the volume of distribution (Vd) following intramuscular (IM) administration of HI-6 (30 mg kg-1). The control t1/2, CL and Vd of HI-offere 27 min, 8.6 ml min-1 kg-1 and 0.34 l kg-1, respectively. These parameters were unaffected by the co-administration of either atropine (0.5 mg kg-1, IM) or atropine and diazepam (0.5 mg kg-1, IM + 0.2 mg kg-1 IV, respectively). Methoxyflurane anesthesia resulted in a significant increase in the HI-6 t1/2 to 61 min concomitant with a decrease in the CL to 4.1 ml min-1 kg-1 with no change in the Vd. The increase in the t1/2 of HI-6 in methoxyflurane anesthetized monkeys is probably the result of a decrease in the clearance rate and, thus, excretion of HI-6 by the kidneys.     

十名志愿者口服维拉帕米缓释片药代动力学和心电图研究

对10名男性受试者单剂量po240mgVer缓释片药代动力学及心电图变化进行研究。血药浓度—时间数据用零级吸收过程的一室模型拟合,其药代动力学参数:T_max5.9±1.6h;C_max118.9±37.2μg·L^-1;T₁ 5.4±1.5h;k₀30.5±17.5μg·L^-1·h^-1;T_1/210.8±4.9h。PR间期延长有显著意义,血药浓度与PR间期变化满足S 型模型,其药效学参数:EC₅₀ 64.6±16.9μg·L^-1; E_max54±11ms;s 1.68±0.66。