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61.
Robert A. Upton Jean-Francois Thiercelin John K. Moore Sidney Riegelman 《Journal of pharmacokinetics and pharmacodynamics》1982,10(2):135-146
Bioavailability studies are commonly undertaken, and most, because they involve subjects taking repeated doses of a drug, contain information on intraindividual variability in pharmacokinetics. However, because in such studies bioavailability itself is unknown, it is difficult to resolve which pharmacokinetic parameters vary within individuals. A mathematical model is presented which permits estimation of variability in clearance and in volume of distribution. When applied to pooled data arising from five theophylline bioavailability studies, this model has given statistical evidence that clearance of theophylline is inherently more variable within individuals (coefficient of variation, 13%) than volume of distribution (8%). As a result, use of the measurement AUC · rather than AUCas a more precise index of bioavailability is justified in studies where is measured with reasonable precision. The model could be applied to estimation of withinbatch within-person variability in bioavailability.Deceased, April 4th, 1981. 相似文献
62.
Theoretical analysis of two models of hepatic drug clearance revealed that one powerful discriminator between them is the effect of changes of hepatic blood flow on either the emergent drug concentration or the availability of a highly extracted compound when operating under linear conditions. Lidocaine (extraction ratio 0.997) was employed in the discriminatory studies. The behavior of this drug under linear conditions (input lidocaine concentrations < 5 mg/ liter) to changes in hepatic blood flow rate (10–16 ml/min per liver) was examined in the perfused rat liver in situpreparation. The steady-state output lidocaine concentration in the blood leaving the liver was predicted better by a well-stirred model than by a parallel tube model. As anticipated, the clearance of a poorly extracted compound, antipyrine (extraction ratio 0.08),was unaltered by changes in hepatic blood flow. These experimental findings, and the data from the literature, point to the acceptance of the well-stirred model, which describes the liver as a well-stirred compartment with the drug in the hepatic venous blood being in equilibrium with that in the liver.Supported in part by National Institutes of Health Grant GM 16496 and the Patent Fund, Graduate Division, University of California, San Francisco.Abstracted in part from a dissertation submitted by K. Sandy Pang to the Graduate Division, University of California, San Francisco, California, in partial fulfillment of the Doctor of Philosophy degree requirements. 相似文献
63.
D. J. Morgan M. J. Cousins D. McQuillan J. Thomas 《European journal of clinical pharmacology》1977,12(5):359-365
Summary Following epidural administration of etidocaine hydrochloride to non-pregnant and pregnant patients, a similar rate of absorption was observed and there was no significant difference in total systemic blood clearance (Clsb) of etidocaine in the two groups. There were no major differences in the urinary excretion of etidocaine and metabolites in 48 h urine in both groups. The ability of pregnant women to form the N-glucuronide of the metabolite ABX (2-amino-2-butyroxylidide) was similar to that of non-pregnant individuals. In vitro experiments showed that the blood/plasma concentration ratio () of etidocaine was significantly higher in pregnant females than in males, presumably due to the lower haematocrit in females. The fraction unbound in plasma (fp) of etidocaine was low in control subjects (mean 0.057) and was not significantly different in pregnant women of 35 to 37 weeks gestation. A marked increase in fp was observed in pregnant women during delivery (mean 0.264). This finding has potentially serious clinical implications because it is the unbound drug in blood which is pharmacologically important. Placental transfer of etidocaine was rapid and the cord/maternal venous blood concentration ratio at delivery (CMb) was, with one exception, always less than unity (mean 0.342). Following epidural administration of etidocaine to pregnant women in labour, measurable concentrations of mono-dealkylated metabolites of etidocaine, PABX (2-N-propylamino-2-butyroxylidide) and EABX (2-N-ethylamino-2-butyroxylidide) were detectable in maternal blood within 5 min and cord blood within 30 min. The CMb for PABX and EABX was 0.401 and 0.658 respectively.List of Abbreviations Used ABX
2-Amino-2-butyroxylidide
- EABX
2-N-Ethylamino-2-butyroxylidide
- PABX
2-N-Propylamino-2-butyroxylidide
- Clsb
Total systemic blood clearance
- Clsp
Total systemic plasma clearance
-
Blood/plasma concentration ratio
- fp
Fraction of unbound drug in plasma
- fpw
Fraction of free drug in plasma water in blood
- Cmb
Cord/maternal venous blood concentration ratio at delivery
- Cmp
Cord/maternal venous plasma concentration ratio at delivery
- t1/2
Terminal phase half-life
- tp
Time of attainment of peak plasma concentration
- E
Mean hepatic extraction ratio
- Q
Liver blood flow 相似文献
64.
目的观察评价盐酸洛美沙星与左氧氟沙星治疗泌尿系感染的疗效及安全性.方法69例病人随机分成两组,治疗组38例,用盐酸洛美沙星0.2g,po,bid;对照组31例,用左氧氟沙星0.1g,po,tid,疗程均为7~14d.结果治疗组临床有效率为92.1%,细菌清除率为91.5%;对照组分别为90.3%和92.5%;两组间无显著性差异(P>0.05).结论盐酸洛美沙星治疗泌尿生殖系感染疗效确切,安全方便,不良反应小. 相似文献
65.
检测肾小球滤过功能的新方法——血清巯基蛋白酶抑制肽C 总被引:6,自引:0,他引:6
目的探讨测定血清巯基蛋白酶抑制肽C(CysC)的方法并评价其检测肾小球滤过功能的价值。方法对照组 2 1例、患者 10 7例 ,用全自动生化分析仪检测CysC、血清肌酐 (Scr)、尿肌酐 ,计算肌酐清除率 (Ccr)。根据Ccr将患者分成 4组。CysC用颗粒增强透射免疫比浊法 ,肌酐用肌氨酸氧化酶 PAP法测定。结果对照组CysC浓度为 1 2 5± 0 14mg/L ,患者组CysC随Ccr下降而升高 ,各组间差异显著 (P <0 0 0 1)。CysC与Ccr的相关性优于Scr与Ccr的相关性。CysC与性别、年龄无相关 ,而Scr男性显著高于女性 (P <0 0 0 1)。受试者工作特征 (ROC)曲线分析 ,CysC区别正常或异常肾功能的准确性较高 ,优于Scr。结论检测肾小球滤过功能CysC较Scr更好 ,不受年龄、性别的影响 ;本法可大批量、快速、准确测定 ,适于临床常规应用。 相似文献
66.
Christopher J. Twelves Nicola A. Dobbs Helen C. Gillies Christopher A. James Robert D. Rubens Peter G. Harper 《Cancer chemotherapy and pharmacology》1998,42(3):229-234
We studied variability in doxorubicin pharmacokinetics in 24 patients with abnormal liver biochemistry tests. Blood samples
were collected after the first cycle of single-agent doxorubicin given as an i.v. bolus and plasma levels were measured by
high-performance liquid chromatography. The relationship between doxorubicin clearance (dose/AUC) and liver biochemistry tests
(AST, bilirubin, albumin, alkaline phosphatase and indocyanine green clearance) was investigated. Patients with a raised bilirubin
level had reduced doxorubicin clearance, but there was no clear relationship between the extent of this elevation and the
reduction in doxorubicin clearance. Doxorubicin clearance was lower in patients with an isolated increase in AST than in those
with normal liver biochemistry, but this difference was not statistically significant. Nevertheless, there was a significant
correlation between reduced doxorubicin clearance and both raised serum AST levels and low indocyanine green clearance. These
pharmacokinetic data suggest that current dose reductions based solely on the extent to which bilirubin is elevated may not
be optimal.
Received: 20 October 1997 / Accepted: 20 January 1998 相似文献
67.
Hiroaki Okamoto Akira Nagatomo Hideo Kunitoh Hiroshi Kunikane Koshiro Watanabe 《Cancer chemotherapy and pharmacology》1998,42(4):307-312
Purpose: Carboplatin doses can be individualized using the formula of Calvert et al. (Calvert formula) dose (mg) = area under the
plasma concentration versus time curve (AUC) · [glomerular filtration rate (GFR) + 25]. Creatinine clearance (Ccr), either
measured by the 24-h method or calculated by the formula of Cockcroft and Gault [Cockcroft-Gault (CG) formula], is often substituted
for the GFR. The CG formula is based on patient weight, age and sex, and the serum creatinine (Cr) concentration. Another
method for predicting carboplatin clearance (CL) using patient characteristics has also been proposed by Chatelut et al. (Chatelut
formula). This study was undertaken to evaluate the performance of the three formulae in predicting standard- and low-dose
carboplatin pharmacokinetics. Methods: A total of 52 patients with advanced lung cancer were enrolled in this pharmacokinetic study; 37 received standard-dose
carboplatin and 25 received low-dose carboplatin. The Cr concentration was measured using an enzymatic assay. The three formulae
were used to predict carboplatin CL. The median absolute percent error (MAPE) for each formula was evaluated by comparing
the calculated and observed CL. For comparison of AUCs, free platinum plasma concentrations were measured at intervals up
to 24 h after carboplatin administration. AUCs were determined and compared with predicted values. Results: In the standard-dose carboplatin group, the MAPEs for the prediction of carboplatin CL from the 24-h Calvert, CG-Calvert
and Chatelut formulae were 13%, 12% and 23%, respectively. In the low-dose carboplatin group, the corresponding MAPEs were
27%, 18% and 44%, respectively. Observed standard-dose carboplatin AUCs after aiming for target AUCs of 5 and 6 mg · min/ml
using the Calvert formula based upon the 24-h Ccr were 5.3 ± 0.8 and 5.9 ± 0.8, respectively, indicating a small and acceptable
bias compared with that predicted from the dosing formula. Conclusions: The pharmacokinetics of standard-dose carboplatin were accurately predicted by the Calvert formula based upon either 24-h
or CG-calculated Ccr, but not by the Chatelut formula. Either CG-calculated or 24-h Ccr can be substituted for the GFR in
the Calvert formula for the determination of individual doses. The poor predictability of the Chatelut formula found in this
study might be the result of a differences in either the Cr assay or the patient population. Therefore, formulae which attempt
to estimate GFR are not necessarily valid if either the Cr assay or the patient population is changed.
Received: 23 July 1997 / Accepted: 16 December 1997 相似文献
68.
Harvey Wong Lois D Lehman-McKeeman Mary F Grubb Scott J Grossman Vasanthi M Bhaskaran Eric G Solon Helen S L Shen Ronald J Gerson Bruce D Car Bitao Zhao Brian Gemzik 《Toxicological sciences》2005,84(2):232-242
4-(3-pentylamino)-2,7-dimethyl-8-(2-methyl-4-methoxyphenyl)-pyrazolo-[1,5-a]-pyrimidine (DMP 904) is a potent and selective antagonist of corticotropin releasing factor receptor-1 (CRF1 receptor) with an efficacious anxiolytic profile in preclinical animal models. In subchronic toxicity studies in Sprague-Dawley rats, DMP 904 produced thyroid follicular cell hypertrophy and hyperplasia, and a low incidence of follicular cell adenoma. The current investigations were designed to determine the mode of action by which DMP 904 disrupts thyroid homeostasis in male rats. Five-day treatment with DMP 904 (300 mg/kg/day) dramatically lowered serum thyroxine (T4) to levels below detectable limits (< 1 microg/dl) by 72 h, with concurrent decreases in triiodothyronine (T3, about a 70% decrease) and increases in thyroid stimulating hormone (TSH; about a three-fold increase). DMP 904 increased [125I]T4 total body clearance (Cl tb) (38.21 +/- 10.45 ml/h) compared to control (5.61 +/- 0.59 ml/h) and phenobarbital-treated rats (7.92 +/- 1.62 ml/h). This increase in Cl(tb) was associated with a significant increase in biliary clearance (Cl bile) of unconjugated [125I]T4 (nearly 80-times control rates) and increased liver:blood ratios of T4, suggestive of enhanced hepatic uptake of T4. A single dose of DMP 904 (200 mg/kg) increased mRNA levels of hepatic cytochrome P450s (CYP 3A1 and CYP 2B1) and UDP-glucuronosyltransferases (UGT 1A1 and UGT 1A2). DMP 904 also induced mRNAs of the canalicular transporter, multi-drug resistance protein-2 (Mrp2) and sinusoidal transporters, organic anion transporting proteins (Oatp1 and Oatp2) within 24 h. Western blot analysis confirmed DMP 904 related increases in Oatp2 protein expression. Collectively, these data suggest that DMP 904 is an agonist of the constitutive androstane receptor (CAR) and pregnane X receptor (PXR) and that the decreased serum levels of T4 and T3 resulted from increased hepatobiliary clearance. However, DMP 904 is distinguished from other compounds associated with similar effects on thyroid hormone homeostasis because its effects were primarily related to increased biliary excretion of unconjugated T4. 相似文献
69.
Pilar Joannon Iris Oviedo Myriam Campbell Juan Tordecilla 《Pediatric blood & cancer》2004,43(1):17-22
BACKGROUND: The objectives of this study were: (1) to analyze the relation of serum methotrexate (MTX) concentration with creatinine clearance, (2) to compare the leucovorin rescue dose administered to the patients based on creatinine clearance, with the one calculated according to serum MTX levels, and (3) to determine MTX-related toxicity. PROCEDURE: Thirty children with high-risk non-B acute lymphoblastic leukemia (ALL) treated according to the national protocol (PINDA 92) based on ALL BFM 90, were randomized to receive consolidation with four doses of either 1 or 2 g/m(2) MTX as a 24-hr infusion, at 2-week intervals (group M1 and M2, respectively). Serum MTX concentrations were measured at 24, 42, and 48 hr after beginning the infusion and were analyzed retrospectively. The creatinine clearance was calculated after 12-hr intravenous hydration prior to each MTX dose. Leucovorin dosage was adjusted according to creatinine clearance. RESULTS: Serum MTX concentrations at 24, 42, and 48 hr after starting the infusion were not related to creatinine clearance in both treatment groups. Leucovorin rescue administered according to creatinine clearance was excessive in 43% in group M1 and in 51% in group M2, as compared to the dose calculated according to serum MTX levels. No serious clinical complications were observed. CONCLUSIONS: These results suggest that creatinine clearance is not a good parameter to calculate leucovorin rescue. MTX-related toxicity in this group of patients receiving a dose of 1 or 2 g/m(2) and rescued with leucovorin without monitoring serum MTX levels was acceptable. 相似文献
70.
TOSHIKO ITAZAWA YUICHI ADACHI MOTOKAZU NAKABAYASHI TATSUYA FUCHIZAWA GYOKEI MURAKAMI TOSHIO MIYAWAKI 《Pediatrics international》2006,48(1):54-57
BACKGROUND: Although viral infection might alter theophylline metabolism in acute asthma, there are some difficulties in detecting infection due to various kinds of viruses in a clinical setting. METHODS: To evaluate the usefulness of assessment of MxA protein in acute asthma exacerbated by viral infection, MxA protein expression in lymphocytes was assayed by flow cytometric analysis in whole peripheral blood in 21 children (aged 0-6 years) receiving continuous theophylline infusion for management of asthma attack. Serum theophylline levels were measured at 24 and 72 h after initiating theophylline infusion. RESULTS: At the beginning of theophylline infusion, 11 children had increased expression of MxA protein, indicating viral infected states. After 24 h continuous infusion, there were no differences in theophylline levels between MxA-negative and MxA-positive groups. After 72 h infusion, the mean theophylline level of MxA-positive children was significantly higher than that of MxA-negative children (9.7 +/- 2.2 microg/mL vs 7.3 +/- 1.6 microg/mL). The ratio of theophylline clearance at 72 h to that at 24 h in the MxA-positive group was significantly lower than that of the MxA-negative group (1.1 +/- 0.2 vs 1.4 +/- 0.1). CONCLUSIONS: Viral infection appeared to affect theophylline metabolism. Flow cytometric assay of lymphoid MxA protein expression in whole blood is an easy and useful method of evaluating viral infection in acute asthma exacerbation. 相似文献