强呋啶栓的药物动力学研究

呋喃氟脲嘧啶(FT207)口服给药分布到直肠靶区的药物浓度低,影响对直肠癌的疗效。为此,我们设计一直肠栓剂,并伍用左旋咪唑及月桂氮(艹卓)酮(Azonc)等合理组方,经家兔直肠给药的药物动力学及组织分布研究证实,FT207血药浓度经时过程为二室模型。其分解产物5—FU血药浓度经时过程为一室模型,药物直肠浓集度显著高于其它组织,比口服相同剂量FT207片高数十倍(FT207)和数倍(5—FU),药物向正常组织的分布减少,对于提高直肠癌疗效降低毒副作用有重要意义。     

HMS-01在小鼠体内的药动学研究

目的 研究HMS-01在小鼠体内的药动学,为后续研究、提供支持。方法 采用液相色谱-串联质谱(LC-MS/MS)技术,建立灵敏、特异的测定血浆等生物样品中HMS-01浓度的分析方法,用建立的方法开展HMS-01在C57BL/6J小鼠体内药动学研究。分别对其进行了3个剂量单次灌胃给药、1个剂量单次静注给药的药动学研究,以获得基本药动学参数。结果 小鼠药代动力学结果表明,HMS-01肠道吸收快,小鼠口服生物利用度中等(50%～70%)。HMS-01在小鼠体内的暴露水平(AUC和c_max)随剂量的增加而增加,其中AUC随剂量的增加成线性相关。HMS-01静脉给药后,在小鼠体内的半衰期不长(约1 h);血浆清除率(CL_tot,p)为2.8L/(h·kg),与小鼠肝血流量相当;表观分布容积(V_SS)为5 L/kg,远大于小鼠总体液。雌雄小鼠经HMS-01口服30、60mg/kg,在AUC和F有显著差异(P<0.05),在c_max、AUC_0-∞、t_1/2、C     

呋喃氟尿嘧啶致突变性的研究

<正> 六十年代以来国内外发现不少药物对人体细胞和生殖细胞遗传结构有影响,染色体畸变不仅能导致遗传病,而且致突变剂多数均是致癌剂。我国近几年来对药物的毒性评价也已发展到三致(畸、突、癌)的研究,以确保用药安全。小鼠骨髓微核试验法是国内外广泛应用的初筛化学物质诱发染色体畸变的一种简便、经济、敏感、快速的有价值方法。本文采用此方法对治胃癌疗效较好的常用药物呋喃氟尿嘧啶(Ftorafur,FT-207)进行了试验。动物用雄性昆明杂种小鼠,体重17-20g。呋喃氟尿嘧啶和注射用环磷酰胺(CTX)均系上药十二厂产品。1.半数致死量测定用改良寇氏法测得FT-207的小鼠口服LD_(50)为1396mg/kg(成年人口服800-1200mg/日)。2.微核式验小鼠分组后灌胃,FT-207均以1%羧甲基纤维素(CMC)作混悬剂,剂量分别为4/5、2/5、1/5和1/10 LD_(50)。同时进行阴、阳性对照试验。各组的药物浓度均相     

单次口服莫达芬尼片在中国健康志愿者的药代动力学

目的研究单次口服莫达芬尼片的药代动力学。方法选择9名健康成年男性受试者分别单次口服100,200,300mg 3个剂量的莫达芬尼片后,用HPLC法测定血中原形药莫达芬尼及代谢产物莫达芬尼酸浓度,用3P97软件进行数据处理,计算药代动力学参数。结果原形药莫达芬尼的药-时曲线符合二房室模型,其主要药代动力学参数的Cmax、AUC0-∞、AUC0-t随剂量加大而增加;t1/2b、tmax、b、CL与给药剂量无关。莫达芬尼片原形药经肾排泄较少,48h经肾累积排泄率分别为(4.44±4.28)%,(3.35±2.20)%和(2.86±1.39)%。主要代谢产物莫达芬尼酸药-时曲线符合二房室模型,48h莫达芬尼酸经肾累积排泄率分别为(33.51±18.90)%,(32.36±19.92)%和(22.88±6.89)%。结论莫达芬尼在100～300mg内,呈线性动力学特征而无饱和性,其消除过程是经肝脏代谢,代谢产物为莫达芬尼酸,代谢产物主要经肾排泄。     

健康人单次口服不同剂量依地普仑片的药动学

目的研究中国健康志愿者单次口服不同剂量依地普仑草酸盐片的体内药动学特点.方法32例受试者单次空腹口服依地普仑草酸盐片,剂量分别为10(n=10),20(n=12),30mg(n=10).用HPLC荧光检测法测定血浆中的依地普仑浓度,用DAS统计软件进行数据处理,计算药动学参数.结果草酸依地普仑片药动学特点符合二房室模型,为线性药动学特点,单次口服依地普仑10,20和30mg的主要药动学参数是Cmax分别为(20.91±4.94),(40.28±10.13)和(57.66±10.51)μg·L-1;Tmax分别为(3.80±1.23),(4.18±0.98)和(4.00±1.49)h;t1/2分别为(34.08±26.58),(36.02±23.68)和(36.95±11.58)h;AUC0～1,分别为(846.8±466.7),(1437.5±535.5)和(2277.5±506.5)μg·h·L-1,AUC0～∞分别为(975.7±622.4),(1587.1±731.2)和(2496.6±707.4)μg·h·L-1.药动学参数的个体间差异较大,CV%最大值为77.99%.女性受试者和男性受试者的血浆清除率(CL/F)及单位剂量的AUC0～1和AUC0～∞值相似.结论中国健康受试者单次口服不同剂量草酸依地普仑的药动学参数具有线性药动学特点.     

多剂量口服阿德福韦酯片在中国健康志愿者的药代动力学和安全性

目的 研究阿德福韦酯(抗病毒药)连续口服后在中国健康人体的药代动力学和安全性.方法 采用随机、双盲、安慰剂对照设计,15名健康志愿者第1天单剂口服阿德福韦酯10 mg;第3天起,每日口服阿德福韦酯10mg 1次,连用5天,用液相色谱-串联质谱法测定血浆和尿液中的药物浓度,计算药代动力学参数.结果 单次和多次口服阿德福韦酯10 mg达稳态后,主要药代动力学参数AUC0-t分别为(205.8±53.1)、(288.8±90.6)ng·h·mL-1;Cmax分别为(21.5±5.1)、(26.7±7.2)ng·mL-1;tmax分别为(1.06±0.41)、(0.94±0.44)h;t1/2分别为(8.12±2.02)、(9.68±2.84)h.单次口服阿德福韦酯48 h内,以原形排入尿中的占给药剂量的(67.8±15.7)%.结论 阿德福韦酯主要经肾脏排泄,连续给药未见蓄积,血药浓度服药后在第4天达稳态,较安全.     

单次静滴双氢青蒿素在健康人体的药代动力学和安全性

目的 研究注射用双氢青蒿素(抗疟有效成分)单次静脉滴注后在中国健康人体的药代动力学和安全性.方法 30名健康受试者随机分为3组,分别单次静脉滴注双氢青蒿素40、80和160 mg,用液相色谱一串联质谱法测定血浆中双氢青蒿素浓度,用WinNonLin软件根据非房室模型计算药代动力学参数.试验过程中密切观察不良事件.结果 3组受试者分别单次静滴双氢青蒿素40、80、160 mg的主要药代动力学参数:Cmax分别为(561.5±127.4)、(1080±210)、(2533±503)ng·mL-1,t1/2分别为(1.69±0.52)、(1.88±0.66)、(1.92±0.53)h,AUC0-t分别为(575.6±98.7)、(1370±289)、(2893±649)ng·mL-1·h;Cmax和AUC0-t与剂量的线性关系良好,随给药剂量的增加成比例增加.试验过程中未出现严重不良事件.结论 单次静滴双氢青蒿素在中国健康受试者的体内过程符合线性药代动力学特征,剂量在40～160 mg较安全.     

非索伪麻缓释片在健康人体中的药代动力学

目的研究中国健康志愿者单次和多次口服非索伪麻缓释片后的药代动力学行为,并评价非索非那定、伪麻黄碱的单次和多次给药药代动力学参数差异。方法 12名健康志愿者单次,多次口服非索伪麻缓释片1片(含盐酸非索非那定60 mg和盐酸伪麻黄碱120 mg),qd,连用8 d,测定给药前和给药后48 h内的血药浓度,用DAS 2.1.1软件计算药代动力学参数。结果单次和多次口服非索伪麻缓释片后药代动力学参数如下,非索非那定的t1/2分别为(10.88±5.67),(7.94±1.80)h,tmax分别为(2.83±0.58),(2.08±0.67)h,cmax分别为(316.42±171.34),(316.50±158.37)ng.mL-1,AUC0-t分别为(1816.33±904.83),(1726.25±741.16)ng.h-1.mL-1;伪麻黄碱的t1/2分别为(6.56±1.04),(8.71±2.38)h,tmax分别为(5.67±2.23),(6.00±2.52)h,cmax分别为(193.58±52.40),(186.17±35.90)ng.mL-1,AUC0-t分别为(3056.92±982.46),(2722.25±602.77)ng.h-1.mL-1。结论单次和多次口服非索伪麻缓释片后,除非索非那定的tmax和伪麻黄碱的t1/2剂量间差异有统计学意义,其他差异均无统计学意义。单次给药后伪麻黄碱的CL/F性别间差异有统计学意义,多次给药后非索非那定的CL/F、AUC0-t性别间差异有统计学意义,其他参数性别间差异无统计学意义。     

阿雷地平肠溶胶囊在中国健康人体内的药代动力学研究

目的:研究中国健康受试者单次和多次口服阿雷地平(AR)肠溶胶囊后阿雷地平(AR)及其主要代谢产物羟基阿雷地平(AR-M1)的药代动力学特征。方法:36名健康受试者,随机分为3组,平行单次口服5,10和20 mg阿雷地平肠溶胶囊的药代动力学研究,10 mg组受试者继续进行多次口服10 mg,qd,连续7 d的药代动力学研究,采用LC-MS/MS法测定血浆中阿雷地平及其主要代谢产物AR-M1的药物浓度,采用DAS 2.1.1软件计算药代动力学参数。结果:单次口服阿雷地平肠溶胶囊5～20 mg后阿雷地平和AR-M1的消除半衰期(t1/2z)分别约为2.0～2.7 h和3.9～5.6 h;达峰浓度(Cmax)随剂量增加呈线性增加,分别为[(2.12±1.14)～(11.34±5.98)μg.L-1]和[(29.41±9.80)～(111.74±24.03)μg.L-1];血药浓度-时间曲线下面积(AUC)也随剂量增加呈线性增加,阿雷地平和AR-M1的AUC0～t分别为[(6.02±2.96)～(30.33±8.88)μg.h.L-1]和[(156.05±32.24)～(776.00±160.47)μg.h.L-1],AUC0～∞分别为[(6.12±2.98)～(30.53±8.89)μg.h.L-1]和[(159.39±33.23)～(785.53±161.92)μg.h.L-1]。多次口服阿雷地平肠溶胶囊10 mg后阿雷地平和AR-M1的t1/2z分别约为2.5和5.5 h,AUC0～t分别为(18.09±5.42)和(604.46±159.66)μg.h.L-1,AUC0～∞分别为(18.25±5.42)和(611.93±162.81)μg.h.L-1。结论:在5～20 mg剂量范围内阿雷地平和AR-M1呈线性药代动力学特征,10 mg多次给药,阿雷地平和AR-M1的Cmax和AUC均较单次给药显著增加,但未见明显蓄积。     

单次口服盐酸伐昔洛韦缓释片在健康人体的药代动力学

目的研究盐酸伐昔洛韦缓释片(抗病毒药)在健康人体内的药代动力学特征。方法12名健康志愿者按拉丁方设计分别口服3种单剂量(600,1200,1800mg)盐酸伐昔洛韦缓释片,用高效液相色谱-紫外检测法测定血浆中盐酸伐昔洛韦活性代谢物阿昔洛韦浓度,用DAS1.0软件计算药代动力学参数。结果12名受试者血药浓度随其单次给药剂量的增加而呈现升高趋势,口服盐酸伐昔洛韦缓释片600,1200,1800mg的AUC0～24分别为(6.61±1.38),(13.38±3.76)和(20.62±8.20)mg.h.L-1;Cmax分别为(1.67±0.37),(3.10±0.87)和(4.73±2.15)mg.L-1,不同剂量组的AUC0-24/dose、Cmax/Dose比值间无显著性差异。结论在600～1800mg内,盐酸伐昔洛韦缓释片在健康人体内过程呈线性药代动力学特征。     

The absorption of cimetidine before and during maintenance treatment with cimetidine and the influence of a meal on the absorption of cimetidine--studies in patients with peptic ulcer disease.

1 The absorption of a single oral dose of cimetidine taken on a fasting stomach or together with a meal was studied in 28 patients before and during 12 weeks treatment with cimetidine. 2 No significant changes in bioavailability were seen during treatment measured as the area under the blood concentration curve (AUC). 3 AUC after a single dose of 400 mg cimetidine was 2.05 times the area after a 200 mg dose. 4 There was a good correlation between AUC and the dose of cimetidine given corrected for body weight (r=0.89). 5 There was no difference in bioavailability if 200 mg cimetidine was taken on a fasting stomach or together with a beef steak meal. 6. During fasting conditions there was a peak in blood concentration at about one hour followed by a second unexplained peak during the third to fifth hour after dose administration. 7 With food the initial rise in blood concentrations was slower and there was only one peak occurring about 2 h after dose administration.     

Dose linearity and steady state pharmacokinetics of the new antiparkinson agent budipine after oral administration.

The dose-dependency of budipine pharmacokinetic characteristics was studied. Eighteen healthy male subjects were given 10, 20 and 30 mg oral single doses according to a randomized, open, 3-period crossover design. Additionally, the steady state conditions were investigated after repeated intake of 10 mg t.i.d for 10 days and compared to the 10 mg single dose. The area under the concentration vs time curve (AUC) and the maximum serum concentration (Cmax) showed a linear increase in line with ascending doses of orally given budipine. Time to maximum serum concentration (tmax) and terminal half-life (t1/2) were independent of the administered dose. As compared to the 10 mg single dose pharmacokinetics, the repeated oral administration of budipine 10 mg t.i.d. resulted in an increase in AUC of 11% and 93% for budipine and its metabolite p-OH-budipine, respectively. In clinical practice, a predictable response in proportion to the dose is to be expected.     

Doxepin-cimetidine interaction: increased doxepin bioavailability during cimetidine treatment

The influence of concurrent cimetidine administration on the disposition of doxepin was evaluated in 10 healthy volunteers. Each subject ingested 100 mg of doxepin on two different occasions, once while otherwise drug free and once while receiving cimetidine, 300 mg every 6 hours. Doxepin absorptive parameters--time to peak doxepin plasma concentration (2.3, control, vs. 2.4 hours during cimetidine co-administration) and peak concentration achieved (43.3. vs. 55.5 ng/ml)--were not changed during cimetidine administration. Likewise, doxepin elimination half-life was similar in the control state (12.5 hours) and during cimetidine administration (13.2 hours). However, doxepin area under the plasma concentration-time curve (AUC) was increased during concurrent cimetidine administration (533 vs. 695 ng/ml . hour; p less than 0.05), resulting in a trend toward decreased doxepin oral clearance (4404 vs. 3278 ml/min; 0.05 less than p less than 0.1). Relative bioavailability during concurrent cimetidine treatment was 123% of that during the control trial. Desmethyldoxepin AUC was no different between trials (478, control, vs. 433 ng/ml . hour during cimetidine ingestion). Plasma protein binding of doxepin was similar between trials (percent unbound; 10.5, control, vs. 11.2%) and therefore did not influence calculated AUC. These data indicate that doxepin relative bioavailability is increased during concurrent cimetidine administration and suggest that doxepin hepatic extraction is impaired by cimetidine after oral administration. During chronic doxepin therapy, addition of cimetidine to a therapeutic regimen may result in increased doxepin plasma concentration.     

Subacute toxicity and toxicokinetics of a new antibiotic,DW-224a,after single and 4-week repeated oral administration in dogs

The subacute toxicity and toxicokinetics of a new fluoroquinolone antibiotic, DW-224a, were evaluated after single (on the 1st day) and 4-week (on the 28th day) oral administration of the drug at doses of 0 (to serve as a control), 10, 30, and 90 mg/kg/d, to male and female dogs (n=3 for male and female dogs for each dose). During the test period, clinical signs, mortality, body weight, food consumption, ophthalmoscopy, urinalysis, hematology, serum biochemistry, gross findings, organ weight and histopathology were examined. The 4-week repeated oral dose of DW-224a resulted in vomiting, salivation, increased serum cholesterol level, and atrophy of thymus and testes. The target organ was determined to be the thymus and testes. The absolute toxic dose of DW-224a was 30 mg/kg and the level at which no adverse effects were observed was 10 mg/kg for both sexes. There were no significant gender differences in the pharmacokinetic parameters of DW-224a for each dose after both single and 4-week oral administration. The pharmacokinetic parameters of DW-224a were dose independent after a single oral administration; the time to reach the peak plasma concentration (T(max)) and the dose-normalized area under the plasma concentration-time curve from time zero to 24 h in plasma (AUC(0-24 h)) were not significantly different among the three doses. The accumulation of DW-224a after 4-week oral administration was not notable at the toxic dose of 90 mg/kg/d. For example, after 4-week administration, the dose-normalized AUC(0-24 h) value at 90 mg/kg/d (7.69, 7.05 microg h/ml) was not significantly greater than that at 10 mg/kg/d. After 4-week oral administration, the dose-normalized C(max) and AUC(0-24 h) at 90 mg/kg/d were not significantly higher and greater, respectively, than those after a single oral administration.     

Effects of rifampicin and cimetidine on pharmacokinetics and pharmacodynamics of lamotrigine in healthy subjects

OBJECTIVE: To study the effects of rifampicin, a potent inducer of the microsomal P450 enzyme system and of specific isoforms of the uridine 5'-diphosphate(UDP)-glucuronyl-transferase enzyme system, and cimetidine, a known inhibitor of the hepatic microsomal cytochrome P450 enzyme system, on pharmacokinetics and pharmacodynamics of lamotrigine in healthy subjects. METHODS: Ten healthy male subjects received a single oral dose of 25 mg lamotrigine after a 5-day pretreatment with (1) cimetidine 800 mg divided into two equal doses, (2) rifampicin 600 mg, or (3) placebo. Serum and urine samples were analyzed using high-performance liquid chromatography. Changes in electroencephalographic (EEG) power were determined up to 48 h after lamotrigine administration. RESULTS: The values of the pharmacokinetic parameters of lamotrigine were: clearance over bioavailability (CL/F) 2.60+/-0.40 l/h, renal clearance (CLR) 0.10+/-0.03 l/h, terminal half-life (t1/2) 23.8+/-2.1 h, mean peak serum concentration (Cmax) 0.29+/-0.02 microg/l, time to reach Cmax (tmax) 1.6+/-0.28 h, and total area under the serum concentration-time curve (AUC0-infinity) 703.99+/-82.31 microg/ ml/min (mean +/- SEM). The amount of lamotrigine excreted as glucuronide was 8.90+/-0.77 mg. Rifampicin significantly increased CL/F (5.13+/-1.05 l/h) and the amount of lamotrigine excreted as glucuronide (12.12+/-0.94 mg), whereas both t1/2 (14.1+/-1.7 h) and AUC(0-infinity) (396.24+/-60.18 microg/ml/min) were decreased (P<0.05). Cimetidine failed to affect pharmacokinetics of lamotrigine. Lamotrigine did not change EEG power. CONCLUSION: Rifampicin altered pharmacokinetics of lamotrigine due to induction of the hepatic enzymes responsible for glucuronidation, while coadministration of cimetidine to ongoing lamotrigine therapy has negligible effects on lamotrigine pharmacokinetics. Lamotrigine administered as a single dose of 25 mg has no effect on EEG power in healthy subjects.     

The relative bioavailability of diclofenac with respect to time of administration.

The pharmacokinetics of diclofenac after a single oral dose (50 mg) were studied in 10 healthy adults on two occasions separated by 2 weeks, once in the morning (dose administered at 07.00 h) and once in the evening (dose at 19.00 h). Peak serum drug concentrations as well as the area under the drug concentration-time curve were significantly less during the night compared with the day (Cmax: 1886 +/- s.d 901 vs 2791 +/- 1565 ng ml-1 and AUC: 2807 +/- 1376 vs 3681 +/- 1986 ng ml-1 h). However, the time to reach peak concentration (tmax) and the half-life of diclofenac (t1/2) were not significantly different on the two occasions. We suggest that the extent of diclofenac absorption is slightly lower following administration in the evening compared with administration in the morning.     

Cimetidine versus famotidine: the effect on the pharmacokinetics of theophylline in rats

The effects of cimetidine and a new, potent H2-antagonist, famotidine, on the single dose pharmacokinetics of theophylline were examined in rats. Male Sprague-Dawley rats (6 rats/group) received an i.v. dose of theophylline (6 mg/kg) alone and in conjunction with an i.v. dose of famotidine (10 mg/kg) or cimetidine (10 mg/kg). Venous blood samples were collected serially for seven hours after theophylline infusion and analyzed for theophylline concentration by HPLC. Concomitant famotidine administration did not alter any of the pharmacokinetic parameters of theophylline (AUC0- infinity; 38.1 +/- 8.7 vs. 38.8 +/- 6.3 micrograms.hr.ml-1), while cimetidine demonstrated a significant reduction in theophylline systemic clearance (0.11 +/- 0.02 vs. 0.16 +/- 0.02 L/hr/kg; p less than 0.001), a 40% prolongation of half-life (2.8 +/- 0.9 vs. 2.0 +/- 0.5 hr), with no change in the volume of distribution (0.39 +/- 0.1 vs. 0.41 +/- 0.13 L/kg). These results suggest that in contrast to cimetidine, famotidine, a non-imidazole H2-receptor antagonist, does not interfere with theophylline disposition in the rat.     

Identification of a single time-point for plasma lansoprazole measurement that adequately reflects area under the concentration-time curve

The objective of this study was to identify a single time-point for plasma lansoprazole measurement that adequately reflects area under the plasma lansoprazole concentration-time curve (AUC) after administration of lansoprazole alone or together with coadministration with CYP mediators. A randomized double-blind placebo-controlled crossover study design in 3 phases was conducted at intervals of 2 weeks. Eighteen healthy Japanese volunteers, comprising 3 CYP2C19 genotype groups, took a single oral 60-mg dose of lansoprazole after three 6-day pretreatments, that is, clarithromycin 800 mg/d, fluvoxamine 50 mg/d, and placebo. Blood samplings (10 mL each) for determination of lansoprazole were taken up to 24 hours after the administration of lansoprazole. Correlation between plasma lansoprazole concentrations at various time points and AUC0-24 were analyzed. Although there were significant differences in the pharmacokinetic parameters of lansoprazole during clarithromycin and placebo among CYP2C19 genotypes, the differences were not found during fluvoxamine. The plasma concentrations 3, 4, 6, and 8 hours after administration (C3, C4, C6, and C8, respectively) were highly correlated with AUC0-24 in coadministration with placebo, clarithromycin, and fluvoxamine (r>0.8, P<0.001). In particular, C6 showed a correlation coefficient of 0.940, 0.992, and 0.953 in coadministration with placebo, clarithromycin, and fluvoxamine, respectively, and was the most appropriate for estimating AUC0-24. The present study demonstrates that AUC of lansoprazole can be estimated by using a single time-point at C6. This method of plasma concentration monitoring at one time-point might be more suitable for AUC estimation than reference to CYP2C19 genotypes, particularly in coadministration of CYP mediators.     

Pharmacokinetics of dihydrocodeine and its active metabolite after single and multiple oral dosing

AIMS: The pharmacokinetics of dihydrocodeine (DHC) and its active metabolite dihydromorphine (DHM) were assessed after a single oral dose of DHC and after increasing doses of DHC at steady-state. Methods Twelve healthy male volunteers (18-45 years, CYP2D6 extensive metabolizers (EMs), MR<1 took a single oral dose (s.d.) of DHC 60 mg after breakfast. After 60 h DHC 60 mg was administered twice daily for 3 days, the dose was increased to 90 mg twice daily for 3 days, the final dose of 120 mg was administered twice daily for 3 days (multiple dose: m.d.). Blood sampling and urine collection: during 60 h after s.d. and during 12 h after m.d. Results No significant differences in the area under the curve (AUC) of both, DHC and DHM could be detected after a single oral dose of 60 mg DHC (AUC (0,infinity)) and during steady-state doses of 60 mg DHC (AUC(0,12 h)). During increasing steady-state doses of DHC, the data showed a dose linearity of AUC, maximal serum concentration (Cmax ) and minimal steady-state serum levels (Cssmin) of both, DHC and DHM (P<0.0001), point estimates of DHC dose corrected AUCs were well within the bioequivalence range (60 mg: 0.989; 90%CI 0.951-1. 028, 90 mg: 0.997; 90%CI 0.959-1.036, 120 mg: 0.977; 90%CI 0.940-1. 016). O-demethylation from DHC to DHM remained constant within the increasing steady-state doses of DHC in the 12 extensive metabolizers of CYP2D6. CONCLUSIONS: In the studied dose range (60-120 mg) the pharmacokinetics of DHC and its active metabolite DHM are linear in EMs of CYP2D6.     

Renal interaction between itraconazole and cimetidine

Renal drug interactions can result from competitive inhibition between drugs that undergo extensive renal tubular secretion by transporters such as P-glycoprotein (P-gp). The purpose of this study was to evaluate the effect of itraconazole, a known P-gp inhibitor, on the renal tubular secretion of cimetidine in healthy volunteers who received intravenous cimetidine alone and following 3 days of oral itraconazole (400 mg/day) administration. Glomerular filtration rate (GFR) was measured continuously during each study visit using iothalamate clearance. Iothalamate, cimetidine, and itraconazole concentrations in plasma and urine were determined using high-performance liquid chromatography/ultraviolet (HPLC/UV) methods. Renal tubular secretion (CL(sec)) of cimetidine was calculated as the difference between renal clearance (CL(r)) and GFR (CL(ioth)) on days 1 and 5. Cimetidine pharmacokinetic estimates were obtained for total clearance (CL(T)), volume of distribution (Vd), elimination rate constant (K(el)), area under the plasma concentration-time curve (AUC(0-240 min)), and average plasma concentration (Cp(ave)) before and after itraconazole administration. Plasma itraconazole concentrations following oral dosing ranged from 0.41 to 0.92 microg/mL. The cimetidine AUC(0-240 min) increased by 25% (p < 0.01) following itraconazole administration. The GFR and Vd remained unchanged, but significant reductions in CL(T) (655 vs. 486 mL/min, p < 0.001) and CL(sec) (410 vs. 311 mL/min, p = 0.001) were observed. The increased systemic exposure of cimetidine during coadministration with itraconazole was likely due to inhibition of P-gp-mediated renal tubular secretion. Further evaluation of renal P-gp-modulating drugs such as itraconazole that may alter the renal excretion of coadministered drugs is warranted.