液相色谱-电喷雾串联质谱法测定人血浆中班布特罗:在药代动力学研究中的应用

目的　建立液相色谱 串联质谱法测定人血浆中班布特罗浓度,研究中国受试者口服该药的动力学特点。方法　血浆样品经液 液萃取后,采用液相色谱电喷雾串联质谱法以选择离子反应监测(SRM)方式进行检测。结果班布特罗的线性范围为0.05 - 4.0ng·mL^-1 ,最低定量浓度为0.05ng·mL^-1 ,该法的日内及日间精密度(RSD)小于8% ,准确度(RE)在±9%范围内。18名中国健康受试者单剂量口服班布特罗10 mg后,主要药动学参数T_max,C_max, T_1/2和AUC_0-t分别为(2.3±1.3)h ,(3.95±2.20 )ng·mL^-1 ,(11.4±6.1)h和(26.85±11.77)ng·h·mL^-1 。结论　该法灵敏度高,操作简便、快速,适用于临床药代动力学研究     

手性和非手性联用色谱法研究尼卡地平对映异构体兔体内过程的差异性

目的研究尼卡地平(NCD)对映体在家兔体内药代动力学和组织分布的差异性。方法生物样品在碱性条件下,正己烷-醋酸乙酯(1:1)提取,用手性和非手性联用色谱法进行分离分析。结果尼卡地平及其对映体分别在反相色谱系统及手性色谱系统中分离良好,浓度为55-550ng·mL^-1线性关系良好。对映体的平均日内、日间RSD分别为5.25%和8.97%,回收率分别为99.99%和97.10%;对映体间主要动力学参数T_max,C_max和AUC,S-NCD为(2.49±0.03)h,(134±2)ng·mL^-1和(1082±32)ng·mL^-1·h,R-NCD为(1.24±0.05)h,(109±2)ng·mL^-1和(778±22)ng·mL^-1·h;在主要脏器和细胞中S-NCD的浓度明显高于R-NCD。药代动力学和靶组织分布均有一定差异性。结论尼卡地平对映体兔体内过程包括代谢动力学和靶细胞浓度分布存在着立体差异性。     

硫酸沙丁胺醇渗透泵控释片的人体药代动力学与生物利用度

目的:研究自制硫酸沙丁胺醇渗透泵控释片与进口控释片的人体药代动力学与生物利用度。方法:利用高效液相色谱荧光检测法,采用交叉实验设计对本品和进口硫酸沙丁胺醇控释片进行人体生物利用度对照研究。结果:硫酸沙丁胺醇控释片与进口硫酸沙丁胺醇控释片的血药浓度曲线下面积AUC 分别为(63.67 ±10.37)ng·h·mL^-1和(60.21 ±11.95) ng·h·mL^-1,最大血药浓度C_max 分别为(8.60 ±1.93) ng·mL^-1 和(8.20 ±1.40)ng·mL^-1,达峰时间T_max 分别为(6.3 ±1.0) h 和(6.8 ±1.3) h,多剂量给药达稳态时血药浓度波动系数FD 分别为1.09 ±0.23 和1.14±0.25。结论:经方差分析和双单侧检验,两种制剂生物等效。     

伏立康唑胶囊人体药动学及相对生物利用度研究

目的 研究健康受试者口服伏立康唑胶囊的药动学和相对生物利用度。方法 20名健康受试者随机服用伏立康唑受试胶囊剂和参比片剂各100 mg,用HPLC-MS/MS测定血浆中伏立康唑的浓度。结果 主要药动学参数,伏立康唑受试制剂与参比制剂的T_max分别为(0.75±0.15)和(0.84±0.25)h,C_max分别为(605.4±136.6)和(595.2±134.7)ng·mL^-1;t_1/2分别为(4.91±1.44)和(5.06±2.06)h,AUC_0-15分别为(1737.6±325.1)和(1750.6±352.8)ng·h·mL^-1。受试制剂与参比制剂的AUC_0-15和C_max经双单侧t检验,T_max经非参数检验,差异均无统计学意义。结论 统计学结果表明,2种制剂生物等效。     

伊伐布雷定及其代谢物的血药浓度测定及人体药动学研究

目的：建立伊伐布雷定（IVA）及其活性代谢产物N-去甲基伊伐布雷定（M1）人体血药浓度的HPLC-MS/MS同时测定方法,研究盐酸伊伐布雷定片经健康受试者口服后IVA及M1的人体药代动力学特征。方法：12名健康受试者单次口服盐酸伊伐布雷定片2.5 mg、5 mg和7.5 mg,多次口服5 mg后,采用HPLC-MS/MS测定不同时间点血浆中IVA和M1浓度,并计算其主要药动学参数。结果：IVA和M1血药浓度标准曲线线性范围分别为0.03~80 ng·mL^-1和0.03~10 ng·mL^-1。单次给药2.5、5、7.5 mg后IVA的C_max分别为（9.661±3.832）、（20.63±9.31）、（34.95±19.46） ng·mL^-1,AUC0-48分别为（42.16±19.53）、（85.86±44.85）、（133.6±65.7） μg·h·L^-1;M1的C_max分别为（1.007±0.189）、（2.683±0.675）、（4.064±1.172） ng·mL^-1,AUC_0-48分别为（10.78±1.35）、（26.02±4.91）、（36.24±7.90） μg·h·L^-1。多次给药5 mg后IVA的稳态平均血药浓度Cav为（6.494±2.385） ng·mL^-1,稳态血药浓度波动度DF为（3.3±0.7）,累积常数R_AUC为（1.1±0.2）;M1的C_av为（1.959±0.186） ng·mL^-1,DF为（1.4±0.3）,R_AUC为（1.5±0.2）。结论：建立的人血浆中IVA和M1的LC-MS/MS同时测定方法适用于人体药代动力学研究。单次给药后,在2.5~7.5 mg范围内IVA和M1均呈线性药动学特征;多次给药5 mg后,IVA人体内的暴露量约增加10%,M1人体内的暴露量约增加50%。     

基于UPLC-MS/MS的新型脂肪酸合成酶抑制剂4k在大鼠体内的药动学研究

目的 建立超高效液相色谱-串联质谱法(UPLC-MS/MS)测定大鼠血浆中新型脂肪酸合成酶抑制剂4k的浓度,并研究其在大鼠体内的药动学特征。方法 12只SD大鼠随机分为2组,分别单次尾静脉注射和灌胃给予4k。以三氯生为内标,建立并验证UPLC-MS/MS测定不同时间点大鼠血浆中4k的浓度,用DAS 2.0软件计算药动学参数。结果SD大鼠单次静脉注射后主要药动学参数为T_1/2 (0.54±0.39)h,T_max 0.033 h,C_max (2 730.72±803.13)ng·mL^-1,AUC_0-∞ (577.72± 174.58)ng·mL^-1·h,Vd (1 241.17±657.98)mL·kg^-1,CL (1 882.67±610.03)mL·kg^-1·h^-1,MRT_0-∞ (0.42±0.19)h。由于灌胃给药后,大鼠体内血药浓度低于定量下限,因此无法进行药动学参数计算。结论 本方法简单准确、快速灵敏,适用于大鼠血浆中4k浓度的测定及其药动学研究。     

盐酸曲美他嗪缓释片在健康人体内的生物等效性研究

目的：评价盐酸曲美他嗪缓释片在中国健康受试者空腹和餐后条件下单剂量给药时的人体生物等效性。方法：采用随机、开放、单剂量、两序列、两周期交叉的试验设计。空腹组和餐后组分别纳入24 例健康受试者,并随机分为两组,每组12例,口服盐酸曲美他嗪缓释片受试制剂（T）或参比制剂（R） 35 mg,第一组按照TR的给药序列,第二组按照RT的给药序列给药。采用高效液相色谱-串联质谱对血浆中曲美他嗪浓度进行测定。利用Win Nonlin 6.4及以上版本和SAS 9.3版本软件进行药代动力学参数的计算和统计分析,并进行生物等效性评价。结果：空腹口服参比制剂和受试制剂后的主要药代动力学参数如下：C_max分别为（69.73±12.86）和（74.43±13.45）ng·mL^-1;T_max均为4.5 h;t_1/2分别为（6.47±0.51） 和（6.38±0.42）h;AUC_0-t分别为（825.74±140.29）和（867.88±126.28）ng·mL^-1·h;AUC_0-∞分别为（832.57±142.73）和（874.50±127.86）ng·mL^-1·h。餐后口服参比制剂和受试制剂后的主要药代动力学参数如下：C_max分别为（80.05±16.67）和（90.40±17.95）ng·mL^-1;T_max均为4.5 h;t_1/2分别为 （6.32±1.02）和（6.17±1.00）h;AUC_0-t分别为（824.61±147.04）和（825.27±154.35）ng·mL^-1·h; AUC_0-∞分别为（831.34±149.00）和（831.43±156.99）ng·mL^-1·h。在空腹和餐后状态下,受试制剂和参比制剂主要药代动力学参数几何均值对应的90%置信区间符合等效范围要求（80.00%~125.00%）。结论：受试制剂和参比制剂在空腹和餐后组口服时均具有生物等效性。     

他克莫司缓释胶囊在Beagle犬体内的药动学与生物等效性研究

目的 研究他克莫司片在beagle犬体内的药动学和生物等效性。方法 采用随机自身交叉对照实验,将6例beagle犬按照先参比制剂后受试制剂、先受试制剂后参比制剂2种给药序列进行随机分配,每组3例,每个周期单次口服3 mg参比制剂或受试制剂,用LC-MS/MS测定样品浓度,再采用WinNonlin 6.3版软件计算药动学参数,比较受试制剂和参比制剂的生物等效性。结果 受试制剂和参比制剂他克莫司药动学参数T_max分别为(1.08±0.41)h和(0.83±0.13)h,C_max分别为(11.63±1.35)ng·mL^-1和(14.83±4.70)ng·mL^-1,AUC_0-48分别为(62.93±32.06)h·ng·mL^-1和(62.89±28.14)h·ng·mL^-1,半衰期t_1/2分别为(10.90±4.26)h和(10.99±3.12)h。Beagle犬口服受试制剂后T_max,t_1/2在受试制剂和参比制剂间无明显差异;峰浓度C_max约为参比制剂给药后的85.34%,90%置信区间为87.21%~102.16%;相对生物利用度(AUC_last,受试/AUC_last,参比)为99.42%,90%置信区间为85.53%~115.56%,表明受试制剂和参比制剂较接近。结论 他克莫司缓释胶囊受试制剂和参比制剂具有生物等效性。     

HPLC-MS/MS法测定人体色甘酸钠血浆浓度及其药代动力学研究

采用HPLC-MS/MS法测定人血浆中色甘酸钠浓度，进行其滴鼻液和鼻用喷雾剂的药代动力学研究并评价其生物等效性。采用高效液相分离系统，流动相为乙酸铵-甲醇(含50%乙腈)(15∶85)，固定相为AGT Venusil XBP C₁₈(250 mm×4.6 mm ID， 5 μm)色谱柱。采用质谱检测系统， ESI离子源， 正离子模式， 多级反应监测(MRM)方式， m/z 469→263.1(色甘酸钠)， m/z 447.2→327.1(内标，普伐他汀钠)。在0.3～20 ng·mL^-1色甘酸钠血药浓度呈线性关系， 定量限为0.3 ng·mL^-1， 回收率在94.1%以上， 日内日间的RSD均小于14.3%。单剂量给药色甘酸钠鼻用喷雾剂或滴鼻液， 其药代动力学参数T_1/2分别为(1.82±0.54)和(1.59±0.52) h； T_max分别为(0.47±0.12)和(0.44±0.15) h； C_max分别为(9.79±4.66)和(10.88±4.05) ng·mL^-1， AUC_{0-5 h}分别为(11.52±3.46)和(12.63±4.23) ng·mL^-1·h。色甘酸钠鼻用喷雾剂相对生物利用度F_r为(93.6±13.8)%。本法灵敏度高， 适用于色甘酸钠治疗药物监测及其药代动力学和生物利用度研究。     

沙丁胺醇气雾剂在健康受试者体内的药代动力学及生物利用度研究

目的研究沙丁胺醇气雾剂在健康受试者体内的药代动力学及其相对于口服水溶液的生物利用度.方法以10名健康男性志愿者为研究对象,采取随机分组、自身对照、开放实验设计,在吸入或口服沙丁胺醇1.2mg后,定时采血,用HPLC方法测定血浆药物浓度,通过PCNONLIN软件进行房室模型拟合,求算药代动力学参数,用非房室模型计算相对生物利用度.结果沙丁胺醇气雾剂的人体内动力学过程符合二室开放模型.两种给药方式的T_max分别为(0.22±0.07)h和(1.8±0.6)h,C_max分别为(3.4±1.1)ng·mL^-1和(3.9±1.4)ng·mL^-1,T_1/2β分别为(4.5±1.5)h和(4.6±1.1)h.AUC_{0-20 min (inhal)}为AUC_{0-20 min (po)} 的7.94倍.相对生物利用度为57.23%.结论所建立的HPLC方法灵敏、专一、准确、精密.沙丁胺醇气雾剂在人体内的吸收过程与口服水溶液有显著差异.     

Alinidine pharmacokinetics following acute and chronic dosing.

1 Alinidine (N-allyl clonidine) pharmacokinetics were investigated in healthy volunteers following acute administration of 40 mg orally and intravenously (i.v.) and chronic administration of 40 mg daily and twice daily for 8 days. 2 After acute oral administration the following values were obtained; Cmax -- 166.5 +/- 18.5 ng/ml at 1.8 +/- 0.7 h (mean +/- s.d., n = 5); AUC -- 1122.9 ng ml-1 h; VdSS -- 190.71 and T1/2 -- 4.2 h, and after i.v. administration: AUC -- 1046.7 ng ml-1 h; VdSS -- 190.71 and T1/2 4.2 h. 3 Clonidine was identified in plasma and urine samples following oral and i.v. administration; clonidine Cmax was 0.26 +/- 0.06 ng/ml at 8.4 +/- 2.2 h and 0.5 +/- 0.2 ng/ml at 4.8 +/- 2.5 following oral and i.v. alinidine respectively. Urinary excretion of clonidine represented 0.1% of the administered dose of alinidine. 4 During administration of alinidine 40 mg daily for 8 days, peak and trough plasma levels reached steady state after day 2 (223.1 +/- 123.9 and 9.03 +/- 6.7 ng/ml respectively). During alinidine 40 mg twice daily for 8 days peak and trough plasma levels on day 2 were 356.2 +/- 92.0 and 80.0 +/- 35.8 ng/ml respectively, these levels did not change (P greater than 0.05) between days 2 and 8. Urine elimination of alinidine did not change (P greater than 0.05) between days 5, 6, 7 and 8. 5 Clonidine plasma concentration following alinidine 40 mg daily and twice daily were 0.47 +/- 0.18 and 0.84 +/- 0.21 ng/ml respectively 2 h after administration on day 2 and did not change (P less than 0.05) between days 2-8. 6 It is unlikely that clonidine formed from alinidine contributes to the pharmacological action of alinidine.     

高效液相色谱法测定血清中依普拉芬浓度及在人体的药代动力学研究

高效液相色谱法测定血清中依普拉芬浓度及在人体的药代动力学研究马晓红许逸刘天培（南京医科大学基础医学院药理教研室，南京２１００２９）依普拉芬（ｉｐｒｉｆｌａｖｏｎｅ，７异丙氧基异黄酮）为一合成的异黄酮衍生物，是新型治疗骨质疏松药物。它主要通过抑制骨吸...     

Absorption of clonazepam after intranasal and buccal administration.

Serum concentrations of clonazepam after intranasal, buccal and intravenous administration were compared in a cross-over study in seven healthy male volunteers. Each subject received a 1.0 mg dose of clonazepam intranasally and buccally and 0.5 mg intravenously. A Cmax of 6.3 +/- 1.0 ng ml-1 (mean; +/- s.d.) was measured 17.5 min (median) (range 15-20 min) after intranasal administration. A second peak (4.6 +/- 1.3 ng ml-1) caused by oral absorption was seen after 1.7 h (range 0.7-3.0 h). After buccal administration a Cmax of 6.0 +/- 3.0 ng ml-1 was measured after 50 min (range 30-90 min) with a second peak of 6.5 +/- 2.5 ng ml-1 after 3.0 h (range 2.0-4.0 h). Two minutes after i.v. injection of 0.5 mg clonazepam the serum concentration was 27 +/- 18 ng ml-1. It is concluded that intranasal clonazepam is an alternative to buccal administration. However, the Cmax of clonazepam after intranasal administration is not high enough to recommend the intranasal route as an alternative to intravenous injection.     

Pharmacokinetics of dipipanone after a single oral dose.

A single oral dose of Diconal (dipipanone HCl 10 mg, cyclizine HCl 30 mg) was given to six volunteers. The mean peak plasma dipipanone concentration was 29 ng ml-1, the time to peak plasma concentration was 1-2 h, the mean elimination half-life was 3.5 h and the mean AUC was 156 ng ml-1 min. Less than 1% of the dose was excreted in urine unchanged over 24 h.     

Pharmacokinetics of oxatomide given percutaneously to healthy volunteers.

The percutaneous absorption of oxatomide gel at 5 per cent concentration was studied after single and repeated administration (85 mg b.i.d.) in six male and six female healthy volunteers, aged 25.7 +/- 0.8 years (mean +/- SEM) weighing 64.4 +/- 4.5 kg and the results compared with those obtained following a single oral dose (30 mg). The measurement of oxatomide was by means of a new sensitive and specific HPLC assay with limits of detection of 0.2 ng ml-1 in plasma and 1.0 ng ml-1 in urine. Poor percutaneous absorption was confirmed by the peak plasma concentrations which were 5.03 +/- 0.79 ng ml-1 following application of the gel for 7 days and 10.08 +/- 1.29 ng ml-1 following oral administration; the corresponding amounts of unchanged oxatomide recovered from 24 h urine collections were 1.42 +/- 0.39 micrograms and 3.93 +/- 0.92 micrograms.     

Pharmacokinetics of digoxin and main metabolites/derivatives in healthy humans

Three healthy, young male volunteers received doses of 0.6 and 1.2 mg of specifically labelled [3H]digoxin each by intravenous (i.v.) bolus injection and oral (p.o.) administration in accordance with a randomized four-way crossover design. Plasma, urine, and feces samples were taken over an interval of 144 h after drug administration. Total radioactivity and individual radioactivity assignable to digoxin and its metabolites were measured. After i.v. administration, the mean +/- SD recovery of total radioactivity, as percent of dose, was complete, urine 81.3 +/- 2.0% and feces 17.1 +/- 2.8%. The mean recovery of digoxin and that of its metabolites in urine was digoxin 75.6 +/- 3.0%, dihydrodigoxin 2.8 +/- 1.6%, digoxigenin bisdigitoxoside 1.6 +/- 0.1%, and additional metabolites 1.5 +/- 0.3%. Judging from the metabolite data in urine and considering the 5% impurity of the administered dose, metabolism of digoxin appeared to be insignificant after i.v. administration. The total and renal clearances of digoxin were, on average, 193 +/- 25 ml min-1 and 152 +/- 24 ml min-1. The mean steady state volume of distribution was 489 +/- 73 L and the mean residence time 41 +/- 5 h. For the metabolites dihydrodigoxin and digoxigenin bisdigitoxoside the mean residence times were on average 35 +/- 9 h and 53 +/- 11 h; the renal clearances were 79 +/- 13 ml min-1 and 100 +/- 26 ml min-1. After p.o. administration, the mean recovery of total radioactivity, as percent of the dose, was also complete, urine 65.7 +/- 1.98% and feces 31.6 +/- 7.6%. The mean recovery of digoxin and that of its metabolites, as percent of dose, in urine was digoxin 51.5 +/- 11.4%, dihydrodigoxin 4.5 +/- 3.9%, digoxigenin bisdigitoxoside 1.9 +/- 0.1%, polar metabolites 5.5 +/- 3.8%, and additional metabolites 1.3 +/- 0.6%. After p.o., as compared to i.v. administration, larger amounts of all the metabolites were formed in accordance with first pass metabolism/degradation. Maximum mean plasma concentrations of 4.3 +/- 2.5 ng ml-1 and 9.5 +/- 1.1 ng ml-1 for digoxin were observed at 40 +/- 10 min after p.o. administration of 0.6 and 1.2 mg of the drug. The mean absolute bioavailability of digoxin from an aqueous solution was 0.67 +/- 0.14. Renal clearance and mean oral residence time for digoxin were on average 176 +/- 28 ml min-1 and 37 +/- 4 h after p.o. administration.(ABSTRACT TRUNCATED AT 400 WORDS)     

Effect of time of dosing on the disposition of oral cibenzoline

Single oral doses of cibenzoline were administered to eight healthy volunteers on two different occasions, once at 8.00 am and once at 10.00 pm, in a randomized crossover design with at least one week separating treatments. A fast was maintained for 12 hours prior to and for 2 hours after the morning dose and the subjects did not lie down for at least 12 hours after dosing. A standard dinner was eaten 3 hours prior to the evening dose, and a fast was maintained for 10 hours after dosing; the subjects laid down 2 hours after dosing for at least 6 hours. Blood was collected at specific times for 72 hours and the total volume of urine voided was collected through 72 hours. Cibenzoline concentrations in plasma and urine were measured by HPLC. Cibenzoline absorption was slower in 7 of the 8 volunteers following the evening dose relative to the morning dose. Mean +/- S.D. tmax for the evening dose was 2.6 +/- 0.5 hours compared to 1.7 +/- 0.8 for the morning dose. The corresponding mean +/- S.D. Cmax following the morning dose was 446 +/- 124 ng ml-1 compared to 402 +/- 114 ng ml-1 after the evening dose. The mean +/- S.D. AUC was 3328 +/- 1101 ng . h . ml-1 after the morning dose and 3561 +/- 1430 ng . h . ml-1 after the evening dose. The harmonic mean half-life was 7.4 hours after both treatments. These data indicated that the total amount of drug absorbed and the elimination rate constant of the drug had not varied between treatments.(ABSTRACT TRUNCATED AT 250 WORDS)     

Bioavailability and cardiovascular safety of Dexatrim (phenylpropanolamine hydrochloride) from a controlled-release caplet

The bioavailability and pharmacokinetics of phenylpropanolamine hydrochloride (PPA HCl) from a Dexatrim controlled-release (CR) caplet and solution was studied. Each subject (n = 12) received either a 75 mg PPA HCl CR caplet once daily or a 25 mg PPA HCl solution given three times a day. All subjects received the medication for 4 consecutive days. On Day 1, the mean +/- SEM, AUC, tmax, and Cmax values were 1651 +/- 127 ng x h ml-1, 4.5 +/- 0.26 h and 143 +/- 13.5 ng ml-1, respectively, for the CR caplet and 1716 +/- 90.3 ng x h ml-1, 1.25 +/- 0.08 h and 126 +/- 5.8 ng ml-1 for the solution, respectively. At steady state (Day 4), the mean +/- SEM, AUC, tmax, and Cmax values were 1832 +/- 101 ng x h ml-1, 4.17 +/- 0.17 h and 151 +/- 6.5 ng ml-1, respectively, for the CR caplet and 2014 +/- 116 ng x h ml-1, 1.33 +/- 0.09 h and 143 +/- 8.7 ng ml-1, respectively, for the solution. The data from Day 1 were fitted to an oral one compartment model with a first order absorption rate constant, kA, first order elimination rate constant, k and lag time. The mean +/- SEM, kA, elimination half-life and lag time for PPA HCl from the CR caplet were 0.488 +/- 0.182 ng h ml-1, 5.84 +/- 1.66 h and 0.394 +/- 0.224 h, respectively. The mean +/- SEM, kA, elimination half-life and lag time for PPA HCl from the solution were 2.87 +/- 1.51 ng x h ml-1, 3.73 +/- 1.21 h, and 0.325 +/- 0.101 h, respectively. The smaller apparent kA and longer elimination half-life for PPA HCl from the CR caplet is due to the slow release of PPA HCl, thereby slowing its absorption producing sustained plasma drug concentrations. Blood pressures (supine and sitting) and heart rates measured at the time of blood sampling after the administration of the PPA HCl dosage forms demonstrated no clinically significant relationship between cardiovascular response and PPA HCl plasma concentration. These data demonstrate the bioavailability and pharmacokinetics of PPA HCl from a CR caplet and an immediate release solution.     

Cimetidine alters pethidine disposition in man

The effect of concurrent cimetidine administration on the disposition of pethidine was investigated in eight healthy male volunteers (18-31 years). The subjects received 70 mg i.v. pethidine HCl doses before and during cimetidine treatment (1200 mg/day p.o.). During cimetidine treatment, pethidine total body clearance (CL) decreased by 22% (0.611 +/- 0.101 [mean +/- s.d.] to 0.474 +/- 0.098 1 kg-1 h, P less than 0.05) and pethidine volume of distribution at steady state (Vss) decreased by 13% (4.79 +/- 0.82 to 4.16 +/- 0.75 l/kg, P less than 0.05). A cimetidine-induced reduction in pethidine oxidation to norpethidine was suggested by a 23% reduction in norpethidine area under the curve from 0 to 24 h (472 +/- 93 to 362 +/- 38 ng ml-1 h, P less than 0.05) and a 29% reduction in peak norpethidine concentration (26.7 +/- 5.3 to 18.9 +/- 1.9 ng/ml, P less than 0.05). There were no significant linear correlations of serum trough cimetidine concentration with percentage reductions in pethidine CL, pethidine Vss, norpethidine AUC (24), or norpethidine peak concentrations. It would appear that the cimetidine-pethidine kinetic interaction may be of sufficient magnitude to be clinically significant. Caution is advised when patients are treated concurrently with these two agents.