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1.
J. T. Backman K. T. Kivistö K. T. Olkkola P. J. Neuvonen 《European journal of clinical pharmacology》1998,54(1):53-58
Objective: To determine the effects of treatment with itraconazole and rifampicin (rifampin) on the pharmacokinetics and pharmacodynamics
of oral midazolam during and 4 days after the end of the treatment.
Methods: Nine healthy volunteers received itraconazole (200 mg daily) for 4 days and, 2 weeks later, rifampicin (600 mg daily) for
5 days. In addition, they ingested 15 mg midazolam before the first treatment, 7.5 mg on␣the␣last day of itraconazole administration,
and 4 days␣later,␣and 15 mg 1 day and 4 days after the last dose␣of␣rifampicin.␣The disposition of midazolam and its α-hydroxy
metabolite was determined and its pharmacodynamic effects were measured.
Results: During itraconazole treatment, or 4 days after, α-hydroxymetabolite the dose-corrected area under the plasma midazolam concentration–time
curve (AUC0–∞) was 8- or 2.6-fold larger than that before itraconazole (i.e. 1707 or 695 versus 277 ng · h · ml−1), respectively. One day after rifampicin treatment, the AUC0–∞ of midazolam was 2.3% (i.e. 4.4 ng · h · ml−1) of the before-treatment value and only 0.26% of its value during itraconazole treatment; 4 days after rifampicin, the AUC0–∞ was still only 13% (i.e. 27.1 ng · h · ml−1) of the before-treatment value. The peak concentration and elimination half-life of midazolam were also increased by itraconazole
and decreased by rifampicin. The ratio of plasma α-hydroxymidazolam to midazolam was greatly decreased by itraconazole and
increased by rifampicin. In addition, the effects of midazolam were greater during itraconazole and smaller 1 day after rifampicin
than without treatment.
Conclusion: Switching from inhibition to induction of cytochrome P450 3A (CYP3A) enzymes causes a very great (400-fold) change in the
AUC of oral midazolam. During oral administration of CYP3A substrates that undergo extensive first-pass metabolism, similar
changes in pharmacokinetics are expected to occur when potent inhibitors or inducers of CYP3A are added to the treatment.
After cessation of treatment with itraconazole or rifampicin, the risk of significant interaction continues up to at least
4 days, probably even longer.
Received: 17 June 1997 / Accepted in revised form: 16 October 1997 相似文献
2.
Objective: To investigate the effects of rifampicin on the pharmacokinetics of itraconazole in humans. Methods: Our study was conducted with six healthy normal volunteers and three AIDS patients. All subjects received a 200 mg single
dose of oral itraconazole on day 1 and day 15 and 600 mg of oral rifampicin once daily from day 2 to day 15. Itraconazole
pharmacokinetics studies were carried out on day 1 (phase 1) and day 15 (phase 2). The limit of detection for itraconazole
concentration was 16 ng · ml–1. Results: Concentrations itraconazole were higher when it was administered alone than when it was administered with rifampicin. Coadministration
of rifampicin resulted in undetectable levels of itraconazole in all subjects except one normal volunteer. The mean AUC0–24 was 3.28 vs 0.39 μg · h · ml−1 in phase 1 and 2, respectively, in healthy normal volunteers. Therefore, the estimated minimum decrease of the mean AUC0–24 of itraconazole in phase 2 was approximately 88% compared with phase 1. The mean AUC0–24 was 1.07 vs 0.38 μg · h · ml–1 in phase 1 and 2, respectively, in AIDS patients. Therefore, the estimated minimum decrease of the mean AUC0–24 of itraconazole in phase 2 was approximately 64% compared with phase 1. Conclusion: Rifampicin has a very strong inducing effect on the metabolism of itraconazole, so that these two drugs should not be administered
concomitantly.
Received: 2 September 1997/Accepted in revised form: 16 December 1997 相似文献
3.
Lack of pharmacokinetic interaction between ropinirole and theophylline in patients with Parkinson's disease 总被引:1,自引:0,他引:1
C. Thalamas A. Taylor C. Brefel-Courbon S. Eagle K. Fitzpatrick O. Rascol 《European journal of clinical pharmacology》1999,55(4):299-303
Objective: Ropinirole and theophylline have the potential to interact, because they use the same hepatic cytochrome P450 (CYP1A2) as
their major metabolic pathway. The present study investigated the effect of steady-state oral theophylline on the pharmacokinetics
of ropinirole at steady state and the effect of steady-state ropinirole on the pharmacokinetics of a single intravenous (i.v.)
dose of theophylline, both in patients with idiopathic Parkinson's disease (PD).
Methods: Pharmacokinetic parameters (AUC and Cmax) for i.v. theophylline were compared before and after a 4-week period of oral treatment with ropinirole (2 mg t.i.d.) in
12 patients with PD. Patients were then maintained at this dose of ropinirole, and oral theophylline was co-administered at
doses of up to 300 mg b.i.d. The parameters AUC, Cmax and tmax for ropinirole were compared before, during and after oral theophylline co-treatment.
Results: Co-administration of ropinirole did not significantly change the pharmacokinetics of i.v. theophylline (mean AUC with and
without ropinirole: 68.6 μg · h−1 · ml−1 and 70.0 μ· h−1 · ml−1, respectively; mean Cmax with and without ropinirole: 11.07 μ g · ml−1 and 11.83 μg · ml−1, respectively). Similarly, there were no significant changes in ropinirole pharmacokinetics when the drug was co-administered
with oral theophylline (mean AUC for ropinirole with and without theophylline: 21.91 ng · h−1 · ml−1 and 22.09 ng · h−1 · ml−1, respectively; mean Cmax for ropinirole with and without theophylline: 5.65 ng · ml−1 and 5.54 ng · ml−1, respectively; median tmax for ropinirole with and without theophylline: 2.0 h and 1.5 h, respectively).
Conclusion: These results suggest a lack of significant pharmacokinetic interaction between the two drugs at current therapeutic doses.
Received: 10 August 1998 / Accepted in revised form: 27 January 1999 相似文献
4.
Objective: To assess the magnitude of the putative effect of atovaquone on the pharmacokinetics of proguanil and to determine whether
the pharmacokinetics of atovaquone are affected by concomitant administration of proguanil, with both drugs administered for
3 days to healthy adult volunteers.
Methods: This was an open-label, randomized, three-way cross-over study, in which 18 healthy volunteers received 400 mg proguanil,
1000 mg atovaquone and 1000 mg atovaquone + 400 mg proguanil. Each treatment was given once daily for 3 days with a 3-week
wash-out period between each occasion. For the assay of proguanil, cycloguanil and atovaquone, blood was sampled before dosing
and at regular intervals over 8 days when proguanil was given, and over 17 days when atovaquone was given.
Results: The geometric mean of the area under the atovaquone plasma concentration-time curve calculated from 0 to 24 h after the
last dose (AUC0→24h) was 180 μg · ml−1 · h following administration of atovaquone alone and 193 μg · ml−1 · h following atovaquone with proguanil. The geometric mean AUC0→24h for proguanil was 6296 ng · ml−1 · h after proguanil alone and 5819 ng · ml−1 · h following proguanil with atovaquone. The corresponding values for the metabolite cycloguanil were 1297 ng · ml−1 · h and 1187 ng · ml−1 · h, respectively. The geometric mean elimination half-life (t1/2) of atovaquone was 57.1 h when given alone and 59.0 h when administered together with proguanil. The corresponding geometric
mean values of t1/2 for proguanil were 13.7 h and 14.5 h. Exploratory statistical analysis showed no important gender effects on the pharmacokinetics
of atovaquone, proguanil, or cycloguanil.
Conclusion: The pharmacokinetics of atovaquone and proguanil and its metabolite, cycloguanil, were not different when atovaquone and
proguanil were given alone or in combination.
Received: 14 October 1998 / Accepted in revised form: 8 February 1999 相似文献
5.
O. A. Aswania S. A. Corlett H. Chrystyn 《European journal of clinical pharmacology》1998,54(6):475-478
Objective: To determine the effects of cimetidine on the steady-state pharmacokinetics and pharmacodynamics of atorvastatin, a 3-hydroxymethylglutaryl
coenzyme A (HMG-CoA) reductase inhibitor.
Methods: Twelve healthy subjects participated in a randomized two-way crossover study. Each subject received atorvastatin 10 mg every
morning for 2 weeks and atorvastatin 10 mg every morning with cimetidine 300 mg four times a day for 2 weeks, separated by
a 4-week washout period. Steady-state pharmacokinetic parameters (based on an enzyme inhibition assay) and lipid responses
were compared.
Results: Pharmacokinetic parameters and lipid responses were similar following administration of atorvastatin alone and atorvastatin
with cimetidine. Mean values for Cmax (the maximum concentration) were 5.11 ng · eq · ml−1 and 4.54 ng eq · ml−1, for tmax (the time to reach maximum concentration) 2.2 h and 1.3 h, for AUC0–24 (area under the concentration-time curve from time 0 h to 24 h) 58.6 ng eq · h · ml−1 and 58.5 ng eq · h · ml−1, and for t1/2 (terminal half-life) 10.1 h and 17.0 h, respectively, following administration of atorvastatin alone and atorvastatin with
cimetidine. Following treatment with atorvastatin alone and atorvastatin with cimetidine, mean values for the percentage change
from baseline for total cholesterol were −29.5% and −29.9%, for low-density lipoprotein (LDL) cholesterol −41.0% and −42.6%,
for high-density lipoprotein (HDL) cholesterol 6.3% and 5.8%, and for triglycerides −33.8% and −25.8%, respectively.
Conclusions: The rate and extent of atorvastatin absorption and the effects of atorvastatin on LDL-cholesterol responses are not influenced
by coadministration of cimetidine.
Received: 17 February 1997 / Accepted in revised form: 3 November 1997 相似文献
6.
Pharmacokinetics and safety of candesartan cilexetil in subjects with normal and impaired liver function 总被引:2,自引:0,他引:2
J. F. W. Hoogkamer C. H. Kleinbloesem M. Ouwerkerk A. Högemann A. Nokhodian W. Kirch E. Weidekamm 《European journal of clinical pharmacology》1998,54(4):341-345
Objective: The influence of liver disease on the pharmacokinetics of candesartan, a long-acting selective AT1 subtype angiotensin II receptor antagonist was studied.
Methods: Twelve healthy subjects and 12 patients with mild to moderate liver impairment received a single oral dose of 12 mg of candesartan
cilexetil on day 1 and once-daily doses of 12 mg on days 3–7. The drug was taken before breakfast. Serial blood samples were
collected for 48 h after the first and last administration on days 1 and 7. Serum was analyzed for unchanged candesartan by
HPLC with UV detection.
Results: The pharmacokinetic parameters on days 1 and 7 revealed no statistically significant influence of liver impairment on the
pharmacokinetics of candesartan. Following single dose administration on day 1, the␣mean␣Cmax was 95.2 ng · ml−1 in healthy subjects and 109 ng · ml−1 in the patients. The AUC0−∞ was␣909 ng.h · ml−1 in healthy volunteers and 1107 ng.h · ml−1 in patients and the elimination half-life was 9.3 h in healthy volunteers and 12 h in the patients. At steady state on day
7, mean Cmax values were similar in both groups (112 vs 116 ng · ml−1); the AUCτ was 880 ng.h · ml−1 in healthy subjects and 1080 ng.h · ml−1 in patients while the elimination half-life was 10 h in healthy subjects and 12 h in the patients with liver impairment.
The AUC0−∞ on day 1 was almost identical to the AUCτ on day 7. A moderate drug accumulation of 20%, which does not require a dose adjustment, was observed following once-daily
dosing in both groups. No serious or severe adverse events were reported.
Conclusion: Mild to moderate liver impairment has no clinically relevant effect on candesartan pharmacokinetics, and no dose adjustment
is required for such patients.
Received: 24 November 1997 / Accepted in revised form: 18 February 1998 相似文献
7.
Objective: To evaluate the effectiveness of Coca-Cola in enhancing the absorption of itraconazole.
Methods: Eight healthy volunteers were randomized to receive two treatment sequences in a two-way crossover design with a 1-week
wash-out period separating each study treatment. Treatment I, the control, consisted of 100 mg itraconazole with 325 ml water.
Treatment II was identical to treatment I, except that itraconazole was administered with 325 ml of Coca-Cola (pH 2.5).
Results: Serum itraconazole concentrations, after administration with Coca-Cola (treatment II), were higher than after administration
with water (treatment I). The mean AUC was 1.12 vs 2.02 μg · h · ml−1, the mean Cmax was 0.14 vs 0.31 μg · ml −1and the mean tmax was 2.56 vs 3.38 h in treatments I and II, respectively.
Conclusion: The absorption of itraconazole can be enhanced by Coca-Cola.
Received: 4 November 1996 / Accepted in revised form: 21 January 1997 相似文献
8.
Lee CT Kuo BI Chen CY Chang FY Lee SD 《European journal of clinical pharmacology》1999,54(11):817-820
Objective: To determine which demographic factors may influence serum gastrin and pepsinogen I (PGI) levels in duodenal ulcer patients
undergoing omeprazole treatment.
Methods: We conducted an outpatient-based prospective study in the Veterans General Hospital, Taipei, to investigate the pharmacological
effects on patients with duodenal ulcers receiving omeprazole treatment for 4 weeks. Sixty-eight patients (61 males/7 females,
aged 25–73 years) with endoscopically confirmed duodenal ulcer were included. Gastrin and pepsinogen I levels were measured
before and after treatment. Demographic factors including age, sex, smoking, ulcer healing and antral Helicobacter pylori colonization/clearance were analyzed, in order to measure their probable influences on serum gastrin and pepsinogen I levels.
Results: Ulcer healing was seen in 92.6% of patients while 48 (70.6%) antral clearances were seen in 66 H. pylori colonized patients at the end of trial. Omeprazole monotherapy led to a marked elevation of serum gastrin (85.8 pg · ml−1, SD 32.0 pg · ml−1 vs 133.9 pg · ml−1, SD 71.6 pg · ml−1, P < 0.01), and pepsinogen I (111.0 ng · ml−1, SD 36.7 ng · ml−1 vs 253.6 ng · ml−1, SD 64.8 ng · ml−1, P < 0.01) levels when measured on day 29. Only patients showing antral H. pylori clearance exhibited an influence on the magnitude of pepsinogen I elevation following omeprazole monotherapy (143.9%, SD
67.3% vs 78.6%, SD 51.2%, P < 0.01). Moreover, the sensitivity and specificity of serum pepsinogen I variations were plotted on a receiving operating
characteristic (ROC) curve. The 140% increased pepsinogen I level yielded a maximum accuracy of 80% specificity or 50% sensitivity
to predict antral H. pylori clearance.
Conclusion: Antral H. pylori clearance is at least partially responsible for the omeprzaole-induced hyperpepsinogenemia I. The magnitude of hyperpepsinogenemia
I probably provides a non-invasive alternative for predicting H. pylori clearance.
Received: 22 August 1996 / Accepted in revised form: 1 October 1998 相似文献
9.
A. Vermeire J. P. Remon M. T. Rosseel F. Belpaire J. Devulder M. G. Bogaert 《European journal of clinical pharmacology》1998,53(5):325-330
Objective: To study the plasma concentrations of morphine and its glucuronides to assess the intra- and interindividual variability
of the disposition of morphine administered by subcutaneous infusion in cancer patients.
Methods: Blood samples were taken repeatedly in eight patients with severe cancer pain who were being treated with morphine (60–3000 mg
per day) via chronic (8–160 days) subcutaneous infusion. Venous blood samples were collected at least weekly and, when possible,
on 3 consecutive days after dose adaptation or any other major change in the patients' treatment. Concentrations of morphine
and its glucuronides in plasma were measured after solid-phase extraction using a validated high-performance liquid chromatography
assay. The stability of the morphine solutions was determined by repeated measurement of the concentrations of morphine and
its degradation products in the solutions.
Results: The morphine concentration in the infusion solutions remained unchanged during storage and infusion. The plasma concentrations
of morphine and its glucuronides were within the ranges reported in the literature. There was, as expected, a large interindividual
variability: from patient to patient, the mean of the normalised plasma concentrations ranged from 0.3 ng · ml−1 · mg−1 to 0.8 ng · ml−1 · mg−1 for morphine, from 1.0 ng · ml−1 · mg−1 to 3.1 ng · ml−1 · mg−1 for morphine-6-glucuronide and from 6.8 ng · ml−1 · mg−1 to 24.3 ng · ml−1 · mg−1 for morphine-3-glucuronide. Intraindividual variability was also important. The residual standard deviation of the mean normalised
plasma concentrations calculated for each patient ranged from 26% to 56% for morphine, from 20% to 51% for morphine-6-glucuronide
and from 20% to 49% for morphine-3-glucuronide. The normalised plasma concentrations of morphine and its glucuronides did
not increase with dose or time, and no explanation for the pronounced pharmacokinetic intraindividual variability was found.
Conclusion: During subcutaneous infusion of morphine, there is a large intra- and interindividual variability of the morphine disposition
which could be of clinical relevance.
Received: 5 August 1997 / Accepted in revised form: 8 October 1997 相似文献
10.
A. Jönsson T. Rydberg G. Sterner A. Melander 《European journal of clinical pharmacology》1998,53(6):429-435
Background: Glibenclamide (Gb) may provoke long-lasting hypoglycaemic reactions, and one of the known risk factors is impaired renal
function. We have demonstrated Gb to have a terminal elimination half-life of 15 h, and the main metabolites have a hypoglycaemic
effect. With few exceptions, detailed studies on second generation sulphonylureas in diabetics with impaired renal function
are lacking. Therefore, we analysed the pharmacokinetics of Gb and its active metabolites, 4-trans-hydroxyglibenclamide (M1) and 3-cis-hydroxyglibenclamide (M2) in this patient group.
Methods: Two groups of 11 diabetic patients with impaired renal function (IRF, iohexol clearance range 7–42 ml · min−1 · 1.73 m−2) or normal renal function (NRF, iohexol clearance range 75–140 ml · min−1 · 1.73 m−2) were compared. A single oral 7-mg dose of Gb was administered after overnight fasting. Serum samples and urine collections
were obtained over 48 h and 24 h, respectively. Concentrations of Gb, M1 and M2 were determined by a sensitive and selective
high-performance liquid chromatography assay.
Results: Peak serum values of M1 (24–85 ng · ml−1 vs 16–57 ng · ml−1), M2 (7–22 ng · ml−1 vs <5–18 ng · ml−1) and M1 + M2 (32–100 ng · ml−1 vs 23–76 ng · ml−1) were higher in the IRF group. AUC and Cmax of Gb were lower and the clearance to bioavailability ratio (CL/f) was higher in the IRF group. AUC and Cmax of M1 were higher and CL/f lower in the IRF group. Much lower amounts of M1 and M2 were excreted in the urine in the IRF
group (7.2% vs 26.4% in 24 h). The fraction of the Gb dose excreted as metabolites (fe(met) 0–24 h), ranged between 0.005
and 0.36 and correlated significantly with renal function measured by iohexol clearance. No other pharmacokinetic differences
were found.
Conclusion: The differences in AUC, Cmax and CL/f of Gb may be explained by a higher free fraction in the IRF group which would increase Gb metabolic clearance. The
inverse findings regarding M1 may be explained by the fact that the metabolites are primarily eliminated by the kidneys. After
a single dose of Gb, neither Gb, M1 nor M2 seemed to accumulate in diabetic subjects with IRF. As only small amounts of M1
and M2 were excreted in the urine, this indicates one or several complementary non-renal elimination routes, e.g. shunting
of metabolised Gb to the biliary excretion route and/or enterohepatic recycling of both metabolites and unmetabolised Gb.
Received: 21 April 1997 / Accepted in revised form: 14 October 1997 相似文献
11.
The cardiac effects of terfenadine after inhibition of its metabolism by grapefruit juice 总被引:2,自引:0,他引:2
C. P. Clifford D. A. Adams S. Murray G. W. Taylor M. R. Wilkins A. R. Boobis D. S. Davies 《European journal of clinical pharmacology》1997,52(4):311-315
Objective: To determine whether the pharmacokinetics and electrocardiographic pharmacodynamics of terfenadine are affected by the concomitant
administration of grapefruit juice.
Methods: Six healthy volunteers were recruited for a balanced cross-over study. Each volunteer received 120 mg terfenadine 30 min
after drinking 300 ml of either water or freshly squeezed grapefruit juice. The alternative treatment was administered on
the second study day 2 weeks later. Measurements of the area under the terfenadine plasma concentration-time curve (AUC),
maximum terfenadine concentration (Cmax) and the time to maximum concentration (tmax) were made, and the corrected QT (QTc) interval was measured from the surface electrocardiogram.
Results: Terfenadine was quantifiable in plasma in all 6 subjects on both study days for up to 24 h post-dosing. The AUC of terfenadine
was significantly increased by concomitant grapefruit administration (median values 40.6 vs 16.3 ng · ml−1 · h), as was the Cmax (median values 7.2 vs 2.1 ng · ml−1). The tmax was not significantly increased and there was no significant change in the median QTc interval despite the increased terfenadine
levels. The 95% confidence interval for the difference in the change in QTc interval at Cmax was −13 to +38 ms.
Conclusion: Administration of grapefruit juice concomitantly with terfenadine may lead to an increase in terfenadine bioavailability,
but the increase observed in this study did not lead to significant cardiotoxicity in normal subjects. However, this does
not exclude the risk of cardiotoxicity in high-risk subjects given greater doses of grapefruit juice over longer periods of
time.
Received: 14 October 1996 / Accepted in revised form: 10 December 1996 相似文献
12.
D. Türck C. A. P. F. Su G. Heinzel U. Busch E. Bluhmki J. Hoffmann 《European journal of clinical pharmacology》1997,51(5):421-425
Objective: The effect of multiple oral doses of meloxicam 15 mg on the pharmacodynamics and pharmacokinetics of warfarin was investigated
in healthy male volunteers. Warfarin was administered in an individualized dose to achieve a stable reduction in prothrombin
times calculated as International Normalized Ratio (INR) values. Then INR- and a drug concentration-time profile was determined.
For the interaction phase, meloxicam was added for 7 days and then INR measurements and the warfarin drug profiles were repeated
for comparison. Overall, warfarin treatment lasted for 30 days.
Results: Warfarin and meloxicam were well tolerated by healthy volunteers in this study. Thirteen healthy volunteers with stable
INR values entered the interaction phase. Prothrombin times, expressed as mean INR values, were not significantly altered
by concomitant meloxicam treatment, being 1.20 for warfarin alone and 1.27 for warfarin with meloxicam cotreatment. R- and S-warfarin pharmacokinetics were similar for both treatments. Geometric mean (% gCV) AUCSS values for the more potent S-enantiomer were 5.07 mg · h · l−1 (27.5%) for warfarin alone and 5.64 mg · h · l−1 (28.1%) during the interaction phase. Respective AUCSS values for R-warfarin were 7.31 mg · h · l−1 (43.8%) and 7.58 mg · h · l−1 (39.1%).
Conclusion: The concomitant administration of the new non-steroidal anti-inflammatory drug (NSAID) meloxicam affected neither the pharmacodynamics
nor the pharmacokinetics of a titrated warfarin dose. A combination of both drugs should nevertheless be avoided and, if necessary,
INR monitoring is considered mandatory.
Received: 13 May 1996 / Accepted in revised form: 29 August 1996 相似文献
13.
O. Spigset K. Granberg S. Hägg Å. Norström R. Dahlqvist 《European journal of clinical pharmacology》1997,52(2):129-133
Objective: The purpose of this study was to investigate whether the disposition of fluvoxamine is associated with the CYP2D6 and CYP2C19
phenotype polymorphisms. Methods: The serum concentration of fluvoxamine was followed for 48 h after oral administration of a single dose of 50 mg fluvoxamine
to five poor metabolizers of the CYP2D6 test drug dextromethorphan, five poor metabolizers of the CYP2C19 test drug mephenytoin,
and five extensive metabolizers of both test drugs. Results: Poor metabolizers of dextromethorphan had significantly higher areas under the serum concentration-time curve than extensive
metabolizers of dextromethorphan (mean 1.31 vs 1.00 μmol · h · l−1). There were no differences between poor and extensive metabolizers of mephenytoin (mean, 1.00 vs 1.15 μmol · h · l−1). Conclusion: The results are consistent with a possible minor to moderate role of CYP2D6, but not CYP2C19, in fluvoxamine metabolism.
Received: 25 April 1996 / Accepted in revised form: 12 November 1996 相似文献
14.
Objective: To investigate the temperature dependency of the dose released and the plasma levels of nicotine from a vapour inhaler.
Methods: In an open, randomised, three-way cross-over pharmacokinetic study 18 healthy subjects inhaled nicotine for 20 min (80 inhalations)
every hour for 10 h (11 administrations) at three different environmental temperatures: 20°, 30° and 40 °C. In the in vitroexperiment,
5, 10, 15 and 20 l air were forced through the inhaler. With a 15 l air volume, the average amount of nicotine released was
1.44, 3.49, 4.80 and 6.99 mg at 10 °C, 22 °C, 29 °C and 40 °C, respectively. The maximum dose released at the highest temperature
(40 °C) and the largest air volume investigated (20 l) was approximately 7.5 mg.
Results: In vivo peak plasma levels obtained at 30° and 40 °C were 29.7 and 34.0 ng · ml−1, compared with 22.5 ng · ml−1 at ambient room temperature (20 °C). At 20 °C, the area under the plasma concentration–time curve (AUC) of the last dosing
interval was 20.5 ng · ml−1 · h. At 30 °C and 40 °C, the AUCs were 26.5 and 30.3 ng · ml−1 · h, respectively. The results thus showed a mean increase of the in vivo AUC by 29% at 30 °C and by 48% at 40 °C compared
with the AUC at 20 °C. These increases should be compared to the in vitro results, showing a mean increase of 59% and 122%,
respectively, at 30° and 40 °C. The in vitro results also showed that a relatively larger fraction of the dose was released
into the first 5 l of air at the higher temperatures, at 40 °C, about 50% of the total amount released into 20 l.
Conclusion: It was concluded that the in vitro/in vivo discrepancy was most probably due to increased aversive effects at elevated temperatures,
causing the subjects to inhale smaller puff volumes. Further, the inhaler would not produce nicotine plasma levels exceeding
those achieved following cigarette smoking, even in a hot climate.
Received: 20 September 1996 / Accepted in revised form: 5 March 1997 相似文献
15.
Thürmann PA Lissner R Struff WG Harder S 《European journal of clinical pharmacology》1999,55(1):49-51
Objective/methods: The pharmacokinetics of the plasma substitute oxypolygelatine (OPG) were studied in 12 healthy volunteers after single-dose
administration of 27 ml · kg−1 body weight, with a maximum of 2000 ml. OPG was determined in plasma and urine over 48 h after the infusion. Peak plasma
OPG concentrations at the end of the infusion were determined to 4.600 (623) μg · ml−1, the area under the plasma concentration/time curve (AUC0∞) was calculated to 70.135 (15.861) μg · h · ml−1.
Results: The model-independently calculated volume of distribution came to 23.1 (4.8) l with a clearance total is (Cltot) of 24.6 (6.8) ml · min−1. The initial half-life according to a three-compartment model came to 0.3 (0.2) h, followed by a distribution half-life of
3.1 (2.6) h and a terminal elimination half-life of 13.4 (2.2) h. Cumulative urinary excretion of OPG was 64% after 48 h.
Conclusion: This low recovery rate may be explained by the distribution of OPG into the extravascular space and subsequent degradation
in tissue sites.
Received: 9 June 1998 / Accepted in revised form: 23 November 1998 相似文献
16.
E. Snoeck V. Piotrovskij P. Jacqmin R. L. Lins A. Van Peer M. Danhof R. Woestenborghs R. Van Gool A. G. Dupont J. Heykants 《European journal of clinical pharmacology》1997,53(1):57-63
Objective: The pharmacokinetics and non-linear red blood cell partitioning of the nucleoside transport inhibitor draflazine were investigated
in 19 healthy male and female subjects (age range 22–55 years) after a 15-min i.v. infusion of 1 mg, immediately followed
by infusions of variable rates (0.25, 0.5 and 1 mg · h−1) and variable duration (2–24 h).
Methods: The parameters describing the capacity-limited specific binding of draflazine to the nucleoside transporters located on
erythrocytes were determined by NONMEM analysis. The red blood cell nucleoside transporter occupancy of draflazine (RBC occupancy)
was evaluated as a pharmacodynamic endpoint.
Results: The population typical value for the dissociation constant K
d (%CV) was 0.648 (12) ng · ml−1 plasma, expressing the very high affinity of draflazine for the erythrocytes. The typical value of the specific maximal binding
capacity Bmax (%CV) was 155 (2) ng · ml−1 RBC. The interindividual variability (%CV) was moderate for K
d (38.9%) and low for Bmax (7.8%). As a consequence, the variability in RBC occupancy of draflazine was relatively low, allowing the justification of
only one infusion scheme for all subjects. The specific binding of draflazine to the red blood cells was a source of non-linearity
in draflazine pharmacokinetics. Steady-state plasma concentrations of draflazine virtually increased dose-proportionally and
steady state was reached at about 18 h after the start of the continuous infusion. The t1/2βaveraged 11.0–30.5 h and the mean CL from the plasma was 327 to 465 ml · min−1. The disposition of draflazine in whole blood was different from that in plasma. The mean t1/2β was 30.2 to 42.2 h and the blood CL averaged 17.4–35.6 ml · min−1.
Conclusion: Although the pharmacokinetics of draflazine were non-linear, the data of the present study demonstrate that draflazine might
be administered as a continuous infusion over a longer time period (e.g., 24 h). During a 15-min i.v. infusion of 1 mg, followed
by an infusion of 1 mg · h−1, the RBC occupancy of draflazine was 96% or more. As the favored RBC occupancy should be almost complete, this dose regimen
could be justified in patients.
Received: 6 February 1997 / Accepted in revised form: 12 May 1997 相似文献
17.
I. Yano A. Takayama M. Takano M. Inatani H. Tanihara Y. Ogura Y. Honda K. Inui 《European journal of clinical pharmacology》1998,54(1):63-68
Objective: To characterize the pharmacokinetics and pharmacodynamics of acetazolamide in patients with transient intraocular pressure
(IOP) elevation and to provide individual patients with the optimal dosage regimen for this drug.
Methods: We studied 17 patients with transient IOP elevation, who were given 62.5–500 mg acetazolamide orally as single or repetitive
doses. Plasma acetazolamide concentration and IOP were measured at approximately 1, 3, 5, and 9 h after the last acetazolamide
administration. Pharmacokinetics and pharmacodynamics were analyzed by nonlinear mixed-effect modeling using the program NONMEM.
Results: The plasma concentration profile of acetazolamide was characterized by a one-compartment model with first-order absorption.
The apparent oral clearance was related to the creatine clearance (CCR) which was estimated by the Cockcroft and Gault equation,
as follows: 0.0468 · CCR l · h−1. The estimated apparent oral volume of distribution, first-order absorption rate constant, and absorption lag time were 0.231 l · kg−1, 0.821 · h−1, and 0.497 h, respectively. IOP after oral acetazolamide administration was characterized by an Emax model. The maximal effect in lowering the IOP (Emax) was 7.2 mmHg, and the concentration corresponding to 50% of the maximal effect (EC50) was 1.64 μg · ml−1. As 70% of Emax was achieved at a plasma concentration of 4 μg · ml−1, this concentration was considered satisfactory for lowering IOP. The recommended dosage was calculated so that the minimum
plasma concentration at steady state exceeded this target concentration; 250 mg t.i.d., 125 mg t.i.d., 125 mg b.i.d., and
125 mg once daily for the patients with CCR values of 70, 50, 30, and 10 ml · min−1, respectively.
Conclusion: Measuring plasma concentrations of acetazolamide and subsequent pharmacokinetic and pharmacodynamic analyses are useful
for estimating its concentration-dependent effectiveness in lowering the IOP in individual patients. The dosage regimen presented
in this study is expected to improve the benefits of acetazolamide pharmacotherapy in most elderly patients with transient
rises in IOP following intraocular surgery.
Received: 10 April 1997 / Accepted in revised form: 21 October 1997 相似文献
18.
S. Hägg O. Spigset T. Mjörndal K. Granberg G. Persbo-Lundqvist R. Dahlqvist 《European journal of clinical pharmacology》1999,55(3):221-226
Objective: To study the suggested pharmacokinetic interaction between erythromycin, a strong inhibitor of CYP3A4, and clozapine.
Methods: Twelve healthy male volunteers received a single dose of 12.5 mg of clozapine alone or in combination with a daily dose
of 1500 mg erythromycin in a randomised crossover study. Clozapine and its metabolites clozapine-N-oxide and desmethyl-clozapine
were measured in serum samples which were collected during a 48 h period and in a sample of the urine secreted over the interval
0–12 h.
Results: There were no significant differences in mean area under the serum concentration time curves (1348 (633) nmol h · 1−1 in the control phase and 1180 (659) nmol h · 1−1 in the erythromycin phase), terminal half-lives (19 (13) h and 15 (6) h, respectively), peak serum concentrations (92 (53) nmol · 1−1 and 77 (40) nmol · 1−1, respectively), time to peak serum concentrations (1.4 (0.7) h and 1.5 (1.0) h, respectively) or apparent oral clearances
of clozapine (34 (15) l · h−1 and 46 (37) l · h−1, respectively). There were no significant differences in partial metabolic clearances to clozapine-N-oxide (5.1 (3.6) l · h−1 and 7.8 (9.4) l · h−1, respectively) or to desmethyl-clozapine (1.5 (1.3) l · h−1 and 1.8 (1.7) l · h−1, respectively) or in renal clearances of clozapine (0.8 (0.5) l · h−1 and 1.0 (0.7) l · h−1, respectively) between the two phases.
Conclusion: These results demonstrate that erythromycin at a clinically relevant dosage does not inhibit the metabolism of clozapine.
Hence, CYP3A4 seems to be of minor importance in the disposition of clozapine in humans at least when clozapine is taken at
a low single dose.
Received: 26 August 1998 / Accepted in revised form: 8 January 1999 相似文献
19.
F. Pea D. Damiani M. Michieli A. Ermacora M. Baraldo D. Russo R. Fanin M. Baccarani M. Furlanut 《European journal of clinical pharmacology》1999,55(5):361-368
Objective: To determine the effect of the coadministration of the multidrug resistance (MDR) modulators cyclosporin A (CyA) alone or
plus dexverapamil (D-Ver) on idarubicin (IDA) pharmacokinetics in patients with acute leukemia.
Methods: Pharmacokinetic studies were performed in 27 patients with a diagnosis of acute myelogenous leukemia (AML), who were being
treated with a combination chemotherapy regimen including idarubicin and cytarabine for the induction of a first remission
(n = 14), or of a second remission (n = 7), or for remission consolidation (n = 6). Of these 27 patients, nine were coadministered CyA and seven were coadministered CyA plus D-Ver as MDR modulators.
Blood was sampled at appropriate intervals after each of the three IDA daily administrations. IDA and idarubicinol (IDAOL)
were assayed by HPLC. Pharmacokinetic evaluations were performed by means of a two-compartment open model with zero-order
absorption and first-order elimination using the WinNonlin pharmacokinetic software package.
Results: CyA markedly increased the area under the concentration time-curve (AUC) of both IDA [558.26 (197.25) μg · h · l−1 vs 315.44 (158.28) μg · h · l−1; P < 0.01] and IDAOL [2896.60 (736.38) μg · h · l−1 vs 1028.49 (603.95) μg · h · l−1; P < 0.001] when coadministered as a single modulator, due to a lower total body clearance (CL) [83.51 (52.44) l · h−1 · m−2 vs 139.65 (69.45) l · h−1 · m−2; NS]. When patients received two MDR modulators simultaneously (D-Ver plus CyA), IDA exposure was essentially the same as
in those of the no inhibitor group [331.29 (95.49) μg · h · l−1 vs 315.44 (158.28) μg · h · l−1; NS], whereas the IDAOL total body exposure was greater than in the no inhibitor group [2030.32 (401.11) μg · h · l−1 vs 1028.49 (603.95) μg · h · l−1; P < 0.01], even if less than in patients receiving CyA as a single MDR modulator (IDA + CyA group) [AUC 2030.32 (401.11) μg · h · l−1 vs 2896.60 (736.38) μg · h · l−1; P < 0.05], suggesting an antagonistic effect against those of CyA on IDA and IDAOL elimination and/or an unpredictable redistribution.
The main pharmacokinetic parameters of IDA, such as CL and volume of distribution at steady state (Vdss), were remarkably affected by the coadministration of CyA or CyA plus D-Ver, but no statistically significant difference
was noted because of IDA pharmacokinetic interpatient variation.
Conclusion: The results show that CyA alone at a dose of 10 mg · kg−1 daily significantly increased systemic body exposure to both IDA and IDAOL in acute leukemia, and suggest that these pharmacokinetic
effects were at least partially decreased when D-Ver was coadministered with CyA. Our findings raise important questions concerning
the need for a dosage adjustment of IDA when MDR modulators are coadministered.
Received: 2 June 1998 / Accepted in revised form: 3 December 1998 相似文献
20.
T. W. B. Gehr D. M. Tenero D. A. Boyle Y. Qian D. A. Sica N. H. Shusterman 《European journal of clinical pharmacology》1999,55(4):269-277
Introduction: Carvedilol, a chiral compound possessing nonselective β- and α1-blocking activity, is used for the treatment of hypertension and congestive heart failure (CHF). The enantiomers of carvedilol
exhibit similar α1-blocking activity; only S-carvedilol possesses β-blocking activity. Carvedilol is primarily hepatically metabolized, with
less than 2% of the dose excreted renally as unchanged drug.
Methods: The pharmacokinetics of carvedilol, R-carvedilol, and S-carvedilol were studied in hypertensive patients (control; n = 13) versus patients with hypertension and advanced renal insufficiency not yet on dialysis [GFR ≤ 30 ml · min−1 (CRI, chronic renal insufficiency), n = 12] following single (12.5 mg, Day 1) and multiple (25 mg once daily, Days 2–9) dosing.
Results: Mean with (SD) AUC(0–24h) (ng · h · ml−1) for carvedilol was 220 (120) and 618 (335) in CRI compared with 165 (83.5) and 413 (247) in controls on Days 1 and 9, respectively,
primarily due to higher R-carvedilol concentrations. Mean with (SD) Cmax (ng · ml−1) for carvedilol were 53.4 (31.4) and 128 (63.3) in CRI compared with 46.7 (23.3) and 104 (58.9) in controls on Days 1 and
9, respectively. The difference in group mean values was characterized by considerable overlap in individual AUC(0–24h) and Cmax values between groups. There was no apparent difference in mean terminal elimination half-life for carvedilol between groups
on each study day. Less than 1% of the dose was excreted in urine as unchanged carvedilol in both groups. Blood pressure and
heart rate declined in both groups to a similar degree.
Conclusion: Compared with controls, average AUC(0–24 h) values for carvedilol were approximately 40% and 50% higher on study Days 1 and 9 in patients with renal insufficiency, primarily
due to higher R-carvedilol concentrations with only a small change (<20%) in S-carvedilol concentrations, the isomer possessing
β-blocking activity. These changes in pharmacokinetics are modest in view of the large interindividual variability. Carvedilol
was well tolerated in both groups. Although the present study cannot provide a final conclusion, based on the results of the
present study, no changes in dosing recommendations for carvedilol are warranted in patients with moderate/severe renal insufficiency.
Received: 26 March 1998 / Accepted in revised form: 30 January 1999 相似文献