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101.
The effects of single oral doses of ketoconazole 400 mg and terbinafine 500 mg on the hepatic microsomal system have been investigated in 8 healthy male volunteers. Microsomal activity caffeine was assessed by following the metabolism of 3 mg/kg bodyweight i.v. administered 1 h after the drug. The inhibitory effect of terbinafine was more pronounced than that of ketoconazole: clearance was decreased from 1.34 ml.kg-1.min-1 in controls to 1.06 and 1.21 ml.kg-1.min-1, respectively, and the corresponding half-life was increased from 5.8 h in controls to 7.6 and 6.7 h, respectively. The apparent volume of distribution remained unchanged. The serum levels of the antimycotics were within the therapeutic range in each subject. Although all three substances are metabolised by microsomes, the kinetic parameters (Cmax, half-life, elimination constant) of the antimycotics were poorly if at all correlated with the elimination of caffeine. 相似文献
102.
Hideari Ihara Denji Shinkuma Yasuji Ichikawa Michio Nojima Shunsuke Nagano Fumihiko Ikoma 《International journal of urology》1995,2(3):151-155
Background: Tacrolimus (FK506) is currently used as the primary immunosuppressant in clinical kidney transplantation in some centers. The purpose of this study was to evaluate the pharmacokinetics of this drug and to see if trough level, which has been used widely in therapeutic drug monitoring, can be used as an appropriate substitute for other pharmacokinetic measurement tests. Methods: The blood concentration-time curve was studied in 10 kidney transplant recipients on 26 Occasions after oral dosage of 2 to 18 mg every 12 hours. Whole blood concentration was measured by two-step irnmunoabsorption assay. Methylprednisolone was used as a concomitant immuno-suppressive drug. Results: The blood concentration-time curves showed remarkable interindividual variation. lntraindividual variation was also found, but the degree of variation was slight compared with interindividual variation. On 17 occasions of measurement in one patient, the dose was significantly correlated with trough (r = 0.684). Cmax (r = 0.838) and AUC0–12 (r = 0.817). In nine patients on nine occasions, however, the dose was not significantly correlated with trough (r = 0.351), Cmax (r = 0.270) or AUC0–12 (r = 0.355). tmax ranged from one to four hours (mean + SD; 2.8 + 1.3) and fluctuated in both intra- and interindividual measurements. In spite of a wide variation in the blood concentration-time-curve patterns, a highly significant linear relationship between trough and Cmax or AUC0–12 was observed in both intraindividual (Cmax, r = 0.876; AUC0–12, r = 0.926) and interindividual (Cmax, f = 0.943; AUC0–12, r = 984) measurements. Concluslons: We conclude that trough level is a practical acceptable indicator of the blood levels of tacrolimus, and can be used to monitor blood concentration. 相似文献
103.
A model for the determination of carbamazepine clearance in children on mono- and polytherapy 总被引:3,自引:0,他引:3
Objective: To derive a model describing carbamazepine (CBZ) clearance in children, in terms of individual patient characteristics.
Methods: One hundred and eighteen steady-state serum carbamazepine concentration measurements were gathered during normal routine
care of 72 compliant out-patients (2.3–16.3 years old). Levels were obtained from patients receiving monotherapy (55%), concomitant
valproate (26%), or concomitant inducers (phenytoin, phenobarbitone; 19%). A one-compartment model was used to fit the data
with the computer programme Nonlinear Mixed Effects Model (NONMEM).
Results: Weight, age and concomitant medication were all important determinants of clearance. The final model for clearance (l · h−1) was: CL = [0.7(WT)0.4] · M, where WT is patient weight (kg) and M is a scaling factor for concomitant medication, with a value of 1 for patients
on CBZ monotherapy or concomitant valproate and 1.4 for those receiving concomitant inducers. For the purposes of this analysis,
bioavailability (f) was assumed to be complete, i.e., f is thus included in the term CL.
Conclusions: CBZ clearance decreased with increasing age. As age and weight were correlated, either variable was a satisfactory predictor.
The influence of both the inducers and valproate on CBZ clearance was as expected. This model, which describes clearance in
terms of patient-specific details, can be used when predicting the maintenance dose required to achieve a target mean steady-state
CBZ concentration in children.
Received: 10 May 1997 / Accepted: 16 February 1998 相似文献
104.
目的研究抗胆碱新药盐酸三环哌酯(TCPN)在小鼠体内的药代动力学及组织分布。方法药代动力学采用放射受体分析法研究,组织中的分布用放射同位素分析法研究。结果小鼠scTCPN后,血液中药物浓度的经时过程符合一级吸收二室模型(T1/2β为2.28h,Tmax为0.125h,Cmax为3.44μg·L-1,Cl为23.0L·kg-1·h-1)。小鼠sc[3H]-TCPN后,分布高峰放射性依次为肾>肝>脑>颌下腺>肠1998-04-03收稿,1998-07-26修回*国家自然科学基金资助课题,No39130090-2作者简介:葛召恒,男,32岁,硕士,助理研究员;阮金秀,男,62岁,研究员,博士生导师,中国毒理学会副理事长,中国药理学会药物代谢专业委员会主任委员>心>肌肉,唯有脑组织的放射性以较高的水平维持较长的时间。预先给小鼠sc不同剂量的QNB,可不同程度地降低脑中放射性的分布。结论TCPN从血中的消除较快,但在脑组织分布时间长,这与药物与脑中M受体的特异性结合有关。 相似文献
105.
R. F. FRYE G. R. MATZKE N. S. JALLAD J. A. WILHELM & G. B. BIKHAZI 《British journal of clinical pharmacology》1996,42(3):301-306
1 The disposition of nalmefene was evaluated in young and elderly normal healthy volunteers. Subjects received either a single 1 mg ( n =18 young; n =11 elderly) or 2 mg ( n =8 young; n =15 elderly) intravenous bolus dose of nalmefene.
2 Following the administration of nalmefene, the initial plasma concentrations were significantly higher in elderly vs young subjects. The higher concentrations were the result of the 30 to 40% smaller central compartment apparent volume of distribution that was observed in the elderly subjects as compared with the young volunteers (2.8±1.1 vs 3.9±1.1 l kg−1 for 1 mg dose). The elderly volunteers also had a significantly shorter distributional half-life ( t1/2λ1 ) than young volunteers (0.7±0.7 vs 1.3±0.8 h for 1 mg dose). No significant differences between groups were observed for the elimination half-life, clearance or steady-state apparent volume of distribution.
3 Although transiently higher nalmefene plasma concentrations were observed in the elderly immediately following drug administration, there was no association between this observation and adverse events. We conclude that no dosage alteration is warranted in elderly patients. 相似文献
2 Following the administration of nalmefene, the initial plasma concentrations were significantly higher in elderly vs young subjects. The higher concentrations were the result of the 30 to 40% smaller central compartment apparent volume of distribution that was observed in the elderly subjects as compared with the young volunteers (2.8±1.1 vs 3.9±1.1 l kg
3 Although transiently higher nalmefene plasma concentrations were observed in the elderly immediately following drug administration, there was no association between this observation and adverse events. We conclude that no dosage alteration is warranted in elderly patients. 相似文献
106.
脂质体阿苯达唑及主要代谢产物的HPLC法和药代动力学研究 总被引:2,自引:0,他引:2
作者报道了动物(鼠)口服脂质体阿苯达唑后血浆、肝脏、包虫囊组织和囊液中阿苯达唑及主要代谢产物阿苯达唑砜和阿苯达唑亚砜的反相HPLC法。同时进行了药物动力学研究和并用西咪替丁后对血、肝药物浓度的影响。结果表明,阿苯达唑在血浆、囊液中的检出限为0.05μg/ml,在肝脏和囊组织中为0.10μg/g;砜和亚砜在血浆、囊液中均为0.01μg/ml,在肝脏和囊组织中均为0.02μg/g。药物动力学结果显示,阿苯达唑脂质体、混悬液及脂质体并用西咪替丁后的体内过程均符合二室模型,混悬液并用西咪替丁后符合单室模型。阿苯达唑脂质体具有一定的缓释及靶向的作用,西咪替丁可能增强阿苯达唑的缓释作用,同时可能加速阿苯达唑亚砜的代谢。 相似文献
107.
Hashimoto Yukiya Sasa Hiroaki Shimomura Masahiro Inui Ken-ichi 《Pharmaceutical research》1998,15(10):1609-1613
Purpose. Tacrolimus, an immunosuppressive agent, has poor and variable bioavailability following oral administration in clinical use. We investigated the contribution of intestinal metabolism to the first pass effect of tacrolimus in rats.
Methods. Tacrolimus was administered intravenously, intraportally or intraintestinally to rats. Blood samples were collected over a 240-min period, and blood tacrolimus concentrations were measured. The extraction ratios of tacrolimus in the intestine and liver were investigated. In addition, the metabolism of tacrolimus in the everted sacs of the small intestine was examined.
Results. The rate of absorption of tacrolimus in the intestine was rapid, and tacrolimus was almost completely absorbed after intestinal administration. The bioavailability of tacrolimus was about 40% and 25% after intraportal and intraintestinal administration, respectively, indicating that tacrolimus is metabolized in both the intestine and the liver. In addition, tacrolimus was significantly metabolized in the everted sacs of the rat intestine.
Conclusions. The present study suggested that the metabolism of tacrolimus in the intestine contributes to its extensive and variable first pass metabolism following the oral administration. 相似文献
108.
A. Fjellestad-Paulsen L. d’Agay-Abensour P. Höglund J.-C. Rambaud 《European journal of clinical pharmacology》1996,50(6):491-495
Objective: The bioavailability of an aqueous solution of 1-deamino-8-D-arginine vasopressin (dDAVP), with and without an enzyme inhibitor,
was studied in six healthy, male volunteers aged 19–34 years, followed for 8 h after each drug administration.
Methods:
For i.v. administration the subjects received 4 μg dDAVP. For intestinal administration 500 μg dDAVP was administered directly,
in two separate sessions, in the first part of the duodenum via a triple-lumen channel tube. In one session a solution of
isotonic polyethylene glycol (PEG) was given as a continuous enteral perfusion. In the other session a solution of PEG and
aprotinin was administered enterally at the constant rate of 5 ml⋅min−1 for 4 h. Plasma dDAVP was measured using a specific, sensitive radioimmunoassay and intestinal juice was collected for measurement
of lipase, chymotrypsin and pH every 30 min for 5 h.
Results:
The intestinal chymotrypsin activity was decreased after perfusion of aprotinin while the lipase activity was not modified.
After i.v. administration, the half-life of elimination of dDAVP was 1.56 h and plasma clearance 1.24 ml⋅min⋅kg−1. The mean bioavailability after duodenal administration of dDAVP + aprotinin was 0.46% compared with 0.09% after duodenal
administration of dDAVP alone. The bioavailability of dDAVP after direct duodenal administration of an aqueous solution was
similar to that after swallowing a tablet in a previous study and increased 5 times when given together with a perfusion of
an enzyme inhibitor.
Received: 27 October 1995/Accepted in revised form: 26 February 1996 相似文献
109.
An expedient, rapid, and sensitive capillary gas chromatographic method for the analysis of l,3-bis(2-chloroethyl)-l-nitrosourea (BCNU) or l-(2-chloroethyl)-3-cyclohexyl-l-nitrosourea (CCNU) in plasma is described. Separation of the underivatized nitrosourea compounds was performed on a 0.33-mm-i.d., 25-m fused-silica, SE-30 capillary column, and detection was carried out using a thermionic N–P-specific detector. The compounds were extracted from plasma with benzene with a yield of >87%. The assay was linear in the ranges of 0.001 to 0.5 and 0.5 to 25 µg/ml for CCNU or 0.003 to 0.50 and 0.5 to 25 µg/ml for BCNU, with correlation coefficients from 0.9914 to 0.9999 and coefficients of variation (CV) of <3.3%. Other antineoplastic agents did not interfere in the assay. The method was employed to study the pharmacokinetics of BCNU in rabbits. The plasma concentration-time curves were fit to a two-compartment model with a mean (SE) , , and total-body clearance of 2.898 (0.913) hr–1, 0.1228 (0.0179) hr–1, and 7.211 (2.862) liters/hr · kg, respectively. Further, the stability of BCNU and CCNU in solution was examined at different temperatures. Both compounds were stable in benzene or acetone (4 to 37°C) but labile in plasma even if refrigerated. The apparent rate constants for degradation of BCNU and CCNU were 0.09921 and 0.02853 hr–1 at 4°C and 5.998 and 2.553 hr–1 at 37°C, respectively. 相似文献
110.
W. Bastain M. J. Boyce L. E. Stafford P. B. Morton D. A. Clarke H. F. Marlow 《European journal of clinical pharmacology》1988,34(5):469-473
Summary The pharmacokinetics of xamoterol, a -adrenoceptor partial agonist under clinical evaluation for the treatment of mild to moderate heart failure, have been studied in 12 healthy male subjects. They received 14 mg i.v. and oral doses of 50 and 200 mg as a tablet and 200 mg as a solution in a 4 way cross-over design.After i.v. dosing the elimination half-life was 7.7 h, the total body clearance was 224 ml·min–1 and the volume of distribution at steady-state (Vss) was 48 l. Sixty-two percent of the dose was recovered unchanged in urine. After oral doses, the absolute bioavailability of xamoterol was shown to be 5% irrespective of whether the dose was administered as a tablet or solution. Peak plasma concentrations occurred at about 2 h for the tablet dose and slightly earlier (1.4 h) for the solution. Peak plasma concentration, AUC and urinary recovery of unchanged drug increased in proportion to dose. The apparent elimination half-life after oral doses (16 h) was significantly longer than that observed after an intravenous dose.Despite the low bioavailability, the degree of inter-subject variability of oral bioavailability was small probably indicating that the controlling factor is the hydrophilic nature of the molecule rather than extensive first pass metabolism or poor dissolution of xamoterol from the tablet formulation. 相似文献