scholarly journals Influence of Bisphosphonates or Recombinant Human Parathyroid Hormone on in Vitro Chemotherapy Sensitivity in Acute Lymphoblastic Leukemia Cells

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4355-4355
Author(s):  
Demi T.C. de Winter ◽  
Jenneke E. van Atteveld ◽  
Jessica G.C.A.M. Buijs-Gladdines ◽  
Rob Pieters ◽  
Sebastian J.C.M.M. Neggers ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Peak Plasma ◽  
Lymphoblastic Leukemia ◽  
Peak Plasma Concentration ◽  
Plasma Concentrations ◽  
Leukemia Cell ◽  
Chemotherapeutic Agents ◽  
Mineral Density ◽  
All Treatment

Abstract BACKGROUND Osteonecrosis and low bone mineral density (BMD) are serious osteogenic side effects of acute lymphoblastic leukemia (ALL) treatment. Bisphosphonates and recombinant human parathyroid hormone (rPTH) tend to be used to ameliorate osteonecrosis-related symptoms as well as to enhance bone mineral density in children with ALL and severe bone fragility. Only one preclinical study on the safety of bisphosphonates during ALL treatment is available, which raises concerns about their impact on leukemic drug sensitivity. Here, we assessed the influence of various bone-modifying agents (zoledronate, pamidronate and rPTH) on in vitro cytotoxicity of chemotherapeutic agents (vincristine (VCR), daunorubicin (DNR), dexamethasone (DEXA), 6-mercaptopurine (6-MP), PEG-asparaginase (PEG-ASP)) and prednisone (PRED) that are commonly used in ALL treatment. METHODS Potential cytotoxic effects of the bone-modifying agents on leukemia cell viability and on in vitro cytotoxic responses of chemotherapeutic agents were tested in various T-cell and B-cell leukemia cell lines using methyl-thiazol-tetrazolium (MTT) assays. Bone-modifying agents were added at concentrations up to a five-fold of their physiological peak plasma concentration. For each assay, 50th percentile of maximal inhibitory concentration was determined. To quantify the combined effects of the bone-modifying agents on chemotherapeutic agent-induced cytotoxicity, median (interquartile range) combination indexes (CI) were calculated. We considered a median CI of < 0.8 as synergism and > 1.2 as antagonism (based on the method of Chou). RESULTS Zoledronate, pamidronate or rPTH in combination with DNR, 6-MP and PEG-ASP showed median CI values between 0.8 and 1.2. Variable inconclusive results were obtained in combination with VCR. Only the combination of a five-fold peak plasma concentration of zoledronate or pamidronate with DEXA resulted in median CI values of 1.15 (range, 1.08-1.48), and 1.34 (range, 1.07-1.62), respectively. Additional experiments using DEXA as well as PRED in combination with one-, three- or five-fold physiological peak plasma concentrations of zoledronate or pamidronate revealed that median CI values stay within 0.8 and 1.2, except for DEXA exposed leukemia cells in combination with a five-fold physiological peak plasma concentration of pamidronate which repeatedly showed a median CI value above 1.2 (1.34, range 1.04-1.86). CONCLUSIONS Zoledronate, pamidronate or rPTH do not seem to influence drug sensitivity of DNR, 6-MP or PEG-ASP, even at a five-fold physiological peak plasma concentration. Nevertheless, our findings suggest a minimal effect of pamidronate on DEXA-induced leukemia cell death. This suggests that even though zoledronate or pamidronate do not seem to negatively influence DEXA- or PRED- induced toxicity in expected physiological concentrations (one- to three-fold physiological peak plasma concentrations), these bone-modifying agents may only be considered with caution in individual cases, and preferably in clinical trial settings before being applied on a large scale in children with ALL. Disclosures No relevant conflicts of interest to declare.

Inhibitory Effect of Citalopram on the Pharmacokinetics of Carvedilol in Rats and in vitro Models

Pharmacology ◽  
2017 ◽  
Vol 100 (5-6) ◽  
pp. 301-307
Author(s):  
Maria Bianca Abrudan ◽  
Dana Maria Muntean ◽  
Daniela Saveta Popa ◽  
Ana-Maria Gheldiu ◽  
Maria Adriana Neag ◽  
...  
Keyword(s):  
Drug Interaction ◽  
Plasma Concentration ◽  
Metabolic Rate ◽  
Liver Microsome ◽  
Peak Plasma ◽  
Peak Plasma Concentration ◽  
Femoral Vein ◽  
Plasma Concentrations ◽  
Drug Drug Interaction

Background/Aims: The aim of this study was to investigate the drug-drug interaction between carvedilol and citalopram based on carvedilol metabolism in vitro and his pharmacokinetics (PKs) in vivo after the oral administration of the single drug and both drugs, and reveal citalopram effects on the PKs of carvedilol. Methods: Each rat was cannulated on the femoral vein, prior to being connected to BASi Culex ABC®. Carvedilol was orally administrated in rats (3.57 mg/kg body weight [b.w.]) in the absence of citalopram or after a pre-treatment with multiple oral doses of citalopram (1.42 mg/kg b.w.). Plasma concentrations of carvedilol were determined using high-performance liquid chromatography-MS at the designated time points after drug administration, and the main PK parameters were calculated by noncompartmental analysis. In addition, effects of citalopram on the metabolic rate of carvedilol were investigated using rat-pooled liver microsome incubation systems. Results: During co-administration, significant increases of the area under the plasma concentration-time curve as well as of the peak plasma concentration were observed. The rat-pooled liver microsome incubation experiment indicated that citalopram could decrease the metabolic rate of carvedilol. Conclusion: Citalopram co-administration led to a significant alteration of carvedilol's PK profile in rats; it also demonstrated, in vitro, these effects could be explained by the existence of a drug-drug interaction mediated by CYP2D6 inhibition.

scholarly journals Assessment of Metabolic Interaction between Repaglinide and Quercetin via Mixed Inhibition in the Liver: In Vitro and In Vivo

Pharmaceutics ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 782
Author(s):  
Ji-Min Kim ◽  
Seong-Wook Seo ◽  
Dong-Gyun Han ◽  
Hwayoung Yun ◽  
In-Soo Yoon
Keyword(s):  
Plasma Concentration ◽  
Liver Microsome ◽  
Peak Plasma ◽  
Peak Plasma Concentration ◽  
Systemic Exposure ◽  
Concurrent Administration ◽  
Time Curve ◽  
Mixed Inhibition

Repaglinide (RPG), a rapid-acting meglitinide analog, is an oral hypoglycemic agent for patients with type 2 diabetes mellitus. Quercetin (QCT) is a well-known antioxidant and antidiabetic flavonoid that has been used as an important ingredient in many functional foods and complementary medicines. This study aimed to comprehensively investigate the effects of QCT on the metabolism of RPG and its underlying mechanisms. The mean (range) IC50 of QCT on the microsomal metabolism of RPG was estimated to be 16.7 (13.0–18.6) μM in the rat liver microsome (RLM) and 3.0 (1.53–5.44) μM in the human liver microsome (HLM). The type of inhibition exhibited by QCT on RPG metabolism was determined to be a mixed inhibition with a Ki of 72.0 μM in RLM and 24.2 μM in HLM as obtained through relevant graphical and enzyme inhibition model-based analyses. Furthermore, the area under the plasma concentration versus time curve (AUC) and peak plasma concentration (Cmax) of RPG administered intravenously and orally in rats were significantly increased by 1.83- and 1.88-fold, respectively, after concurrent administration with QCT. As the protein binding and blood distribution of RPG were observed to be unaltered by QCT, it is plausible that the hepatic first-pass and systemic metabolism of RPG could have been inhibited by QCT, resulting in the increased systemic exposure (AUC and Cmax) of RPG. These results suggest that there is a possibility that clinically significant pharmacokinetic interactions between QCT and RPG could occur, depending on the extent and duration of QCT intake from foods and dietary supplements.

Application of Statistical Tooling Techniques for Designing of Carvedilol Nanolipid Transferosomes and its Dermatopharmacokinetic and Pharmacodynamic Studies

2020 ◽  
Vol 8 (6) ◽  
pp. 452-470
Author(s):  
Brito R. Selvaraj ◽  
Seshaiah K. Sridhar ◽  
Bhaskar R. Kesavan ◽  
Sucharitha Palagati
Keyword(s):  
Particle Size ◽  
Plasma Concentration ◽  
Dosage Form ◽  
Peak Plasma ◽  
Peak Plasma Concentration ◽  
Entrapment Efficiency ◽  
Transdermal Patch ◽  
In Vitro Drug Release

Background: The hypothesis is to augment the bioavailability and therapeutic potential of low bioavailable Carvedilol (25-35%) through Nanostructured Lipid Carrier (NLC) loaded Transdermal patch (Nanolipid Transferosomes). Methods: Box-Behnken design was designed to formulate NLC through a hot homogenization technique. About 17 formulations (C1-C17) were formulated by varying the critical material attribute and critical process parameter. Optimization was done based on its critical quality attributes like particle size, zeta potential and entrapment efficiency. Selected NLC (C16) has been fabricated into a transdermal patch through solvent evaporation technique and estimated for thickness, weight variation, moisture content, folding endurance, drug content, in vitro drug release, ex vivo skin permeation studies 48 hrs, in vitro drug release kinetic studies and skin irritation studies. In vivo pharmacokinetics and pharmacodynamic study parameters were compared between carvedilol loaded NLC transdermal patch and a conventional formulation (Coreg CR). Results: NLC (C16) was selected as the best formulation based on desirable, less particle size (201.1 ± 2.02 nm), more zeta potential (-37.2 ± 1.84mV) and maximum entrapment efficiency (87.54 ± 1.84%). Experimental investigations of in vivo dermatopharmacokinetic data shown statistically significant changes (p<0.05) in the parameter (increased AUC0-α, MRT with decreased Cmax, Tmax) when administered through the transdermal patch and on compared to the conventional dosage form. It was observed that there was a significant change with p<0.05 among the pharmacokinetic factors of conventional Carvedilol formulation, Carvedilol NLC and Carvedilol NLC loaded Transdermal patch with a maximum time of peak plasma concentration (Tmax) of 4 hrs, 8 hrs and 8 hrs; maximum peak plasma concentration (Cmax) of 0.258 μg/ml, 0.208 μg/ml and 0.108 μg/ml. Area Under Curve (AUC0-α) was established to be 125.127 μg/ml/h, 132.576 μg/ml.h and 841.032 μg/ml.h. Mean Residence Time (MRT0- α) of the drug was established to be 17 hrs, 19 hrs and 82 hrs, respectively. This data reveals the impact of NLC on the enhancement of bioavailability through a transdermal patch. In vivo pharmacodynamic studies confirm that NLC loaded transdermal patch (Nanolipid Transferosomes) shows a significant control in blood pressure for 48 hrs when compared to the conventional dosage form. Conclusion: This research data concludes that NLC loaded transdermal patch (Nanolipid Transferosomes) was a suitable candidate to enhance the bioavailability of low bioavailable drug-like Carvedilol. Lay Summary: It was inferred from the literature that NLC filled transdermal patches were a novel strategy to increase the solubility and permeability of Carvedilol, which has less bioavailability. It reveals that there was no reproducible preparation for the NLC. It also reveals that the option of formulation and process parameters for the formation of NLC is not clearly justified. On account of this, an uniquely validated and optimized formulation technique was developed for NLC with low soluble and poorly bioavailable carvedilol, tested in Albino wistar rats for enhancement of bioavailability, the same study has been performed and proved.

Trigeminal Neuralgia: Time Course of Pain in Relation to Carbamazepine Dosing

Cephalalgia ◽  
1981 ◽  
Vol 1 (2) ◽  
pp. 91-97 ◽  
Author(s):  
Torbjörn Tomson ◽  
Karl Ekbom
Keyword(s):  
Plasma Concentration ◽  
Trigeminal Neuralgia ◽  
Time Course ◽  
Peak Plasma ◽  
Peak Plasma Concentration ◽  
Plasma Concentrations ◽  
Significant Drop ◽  
Idiopathic Trigeminal Neuralgia ◽  
Full Effect ◽  
Pain Distribution

Eight in-patients with idiopathic trigeminal neuralgia (TN) were studied while receiving carbamazepine (CBZ) treatment. The aim was to study diurnal pain distribution, its relation to CBZ dosing and plasma concentration and the effect of decreasing the dose. All pain attacks were registered by the patients at three-hour intervals. CBZ was given b.i.d. in a single blind manner with the patient unaware of dose and dose changes. Plasma concentrations of CBZ were followed every fourth hour during a period of altogether sixteen dosage intervals. The diurnal pain distribution revealed marked intra-individual similarities with pain-free nights and a significant drop in pain during mid-day hours. The latter coincided in time with the peak plasma concentration of CBZ, thus indicating an effect of plasma concentration fluctuations on pain relief. Shorter dosage intervals might therefore be beneficial in problem cases. A significant increase in pain was detected within six to nine hours after a dose reduction, whereas the full effect of the dose change seemed to be established only after one day.

scholarly journals Pharmacokinetic Profile of Oral Administration of Mefloquine to Clinically Normal Cats: A Preliminary In-Vivo Study of a Potential Treatment for Feline Infectious Peritonitis (FIP)

Animals ◽  
2020 ◽  
Vol 10 (6) ◽  
pp. 1000
Author(s):  
Jane Yu ◽  
Benjamin Kimble ◽  
Jacqueline M. Norris ◽  
Merran Govendir
Keyword(s):  
Plasma Concentration ◽  
Peak Plasma ◽  
Peak Plasma Concentration ◽  
Plasma Concentrations ◽  
Pharmacokinetic Profile ◽  
Feline Calicivirus ◽  
Potential Treatment ◽  
Feline Infectious Peritonitis ◽  
Feline Coronavirus

The pharmacokinetic profile of mefloquine was investigated as a preliminary study towards a potential treatment for feline coronavirus infections (such as feline infectious peritonitis) or feline calicivirus infections. Mefloquine was administered at 62.5 mg orally to seven clinically healthy cats twice weekly for four doses and mefloquine plasma concentrations over 336 h were measured using high pressure liquid chromatography (HPLC). The peak plasma concentration (Cmax) after a single oral dose of mefloquine was 2.71 ug/mL and time to reach Cmax (Tmax) was 15 h. The elimination half-life was 224 h. The plasma concentration reached a higher level at 4.06 ug/mL when mefloquine was administered with food. Adverse effects of dosing included vomiting following administration without food in some cats. Mild increases in serum symmetric dimethylarginine (SDMA), but not creatinine, concentrations were observed. Mefloquine may provide a safe effective treatment for feline coronavirus and feline calicivirus infections in cats.

Etoposide achieves potentially cytotoxic concentrations in CSF of children with acute lymphoblastic leukemia.

1996 ◽  
Vol 14 (2) ◽  
pp. 399-404 ◽  
Author(s):  
M V Relling ◽  
H H Mahmoud ◽  
C H Pui ◽  
J T Sandlund ◽  
G K Rivera ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Plasma Concentration ◽  
Protein Concentration ◽  
Lymphoblastic Leukemia ◽  
Plasma Concentrations ◽  
Treatment Regimens ◽  
Paired Samples ◽  
First Remission ◽  
Csf Levels

PURPOSE Although epipodophyllotoxins are commonly used in contemporary treatment regimens for acute lymphoblastic leukemia (ALL), their potential role in CNS-directed therapy has received little attention. We prospectively studied 20 children during initial remission of ALL and 16 children at relapse to assess CSF penetration of etoposide. METHODS Simultaneous plasma and CSF concentrations were assessed at a median of 2.8 hours (range, 0.4 to 5.3) after an intravenous (i.v.) or oral dose in 41 paired samples. RESULTS Etoposide given at 300 mg/m2 i.v. to patients during first remission and at 50 or 25 mg/m2 orally to those in relapse resulted in median CSF levels of 0.175 mumol/L (range, .066 to 2.12), 0.011 mumol/L (range, .004 to .032), and 0.007 mumol/L (range, .003 to .014), respectively. The CSF etoposide concentration was > or = 10 nmol/L in 20 of 20, five of 10, and two of 11 courses following 300 mg/m2 i.v., 50 mg/m2 orally, and 25 mg/m2 orally, respectively, and was positively related to both the concurrent etoposide plasma concentration (R2 = .64) and to dose (R2 = .73). The median ratio of CSF to plasma concentration was 0.30% (range, 0.09% to 3.12%), which was not related to dose, plasma concentration, or time postdose at which samples were obtained, but was positively correlated with the CSF protein concentration (R2 = 0.43, P = .006). Both the absolute etoposide CSF concentrations (P = .008) and the ratio of CSF to plasma concentrations (P = .023) were higher among first-remission patients who had CSF leukemic blasts at diagnosis compared with those without CSF blasts. CONCLUSION Because etoposide concentrations as low as 10 nmol/L may be cytotoxic in vitro, prolonged daily oral low-dose (50 mg/m2) or conventional i.v. doses of etoposide may contribute to successful CNS-directed therapy in children with ALL.

Comparative Bioequivalence and Efficacy of Two Sustained-Release Procainamide Formulations in Patients with Cardiac Arrhythmias

1988 ◽  
Vol 22 (7-8) ◽  
pp. 554-558 ◽  
Author(s):  
Daniel E. Hilleman ◽  
Albert J. Patterson ◽  
Syed M. Mohiuddin ◽  
Brian G. Ortmeier ◽  
Christopher J. Destache
Keyword(s):  
Plasma Concentration ◽  
Sustained Release ◽  
Cardiac Arrhythmias ◽  
Peak Plasma ◽  
Statistical Significance ◽  
Peak Plasma Concentration ◽  
Plasma Concentrations ◽  
Blood Sampling ◽  
Time Curve ◽  
Alternate Test

This investigation evaluated the bioequivalence and efficacy of two sustained-release procainamide products. Ten patients with cardiac arrhythmias were randomized to product A (Procan-SR) or product B (Pronestyl-SR). After nine doses of study medication, plasma procainamide and N-acetylprocainamide concentrations were obtained to determine the area under the concentration versus time curve at steady state (AUCss), mean plasma concentration (Cavss), the observed peak plasma concentration (Cmaxss), the observed trough plasma concentration (Cminss), and the apparent time to achieve Cmaxss (tmax). The products were compared on a milligram-equivalent (adjusted) basis. Following completion of blood sampling, patients were crossed-over to the alternate product. There was no washout between treatments. After nine doses of the alternate test medications, blood sampling was repeated. Differences in AUCss, Cavss, Cmaxss, tmax, and intradose peak/trough ratios were not statistically significant. Within-group variability in AUCss, Cavss Cmaxss, and tmax was greater with product B, but this trend did not reach statistical significance. Antiarrhythmic efficacy was not significantly different between the two treatments. Although the greater bioequivalence, lesser variability, and the greater number of tablet dosage sizes would favor product A, patients stabilized on a particular brand of sustained-release procainamide should not be switched to another product without careful monitoring. One patient in this study developed nonsustained ventricular tachycardia with low procainamide plasma concentrations after being switched from product A to product B.

scholarly journals Pharmacokinetics of Lornoxicam in rabbits after single intravenous bolus and intramuscular administrations

2016 ◽  
Vol 4 (1) ◽  
pp. 66
Author(s):  
Abubakr El-Mahmoudy
Keyword(s):  
Plasma Concentration ◽  
Half Life ◽  
Peak Plasma ◽  
Peak Plasma Concentration ◽  
Plasma Concentrations ◽  
Pharmacokinetic Profile ◽  
Volume Of Distribution ◽  
Bolus Administration ◽  
Systemic Bioavailability ◽  
Total Body

The pharmacokinetics of lornoxicam (a non-steroidal anti-inflammatory drug) at a dose of 0.4 mg/Kg body weight was evaluated after single intravenous (i.v.) and intramuscular (i.m.) bolus administrations in rabbits. An HPLC assay using pure lornoxicam base as a standard was used to measure its concentrations in plasma at prefixed time points up to 12 hours post administration. Following an i.v. bolus injection, the plasma concentration-time curves of lornoxicam were best represented by two-compartment open model. The drug was rapidly distributed and moderately eliminated with half-lives of distribution (t1/2α) and elimination (t1/2β) of 0.238 and 2.611 h, respectively. The volume of distribution was large with (Vdss) value of 1.499 L. The total body clearance (ClB) was 0.413 L/h. After i.m. bolus administration of the same dose, lornoxicam was moderately and completely absorbed in rabbits with an absorption half-life (t½ab) of 1.228 h with peak plasma concentration (Cmax) of 0.463 μg/mL attained at 1.512 h (Tmax) and systemic bioavailability of 99.79%. The elimination half-life following i.m. administration was 2.283 h. The extent of plasma protein binding percent was 98.9%. The study recommends the use of lornoxicam in rabbits because of its good pharmacokinetic profile indicated by good absorption, bioavailability and plasma concentrations.

EFFECT OF THE CALCIUM CHANNEL BLOCKER, NIFEDIPINE, ON HAEMOSTASIS, CLOTTING, AND THROMBOLYSIS EX VIVO.

1987 ◽  
Author(s):  
M Rademaker ◽  
R H Meyrick Thomas ◽  
J D Kirby ◽  
I B Kovaos
Keyword(s):  
Oral Dose ◽  
Calcium Channel ◽  
Ex Vivo ◽  
Peak Plasma ◽  
Peak Plasma Concentration ◽  
Plasma Concentrations ◽  
Channel Blockers ◽  
Clotting Time ◽  
Polyethylene Tubing

Nifedipine, as other calcium channel blockers, has been shown to inhibit platelet aggregation induced by various agonists in vitro. The therapeutic relevance of these findings are, however, questionable, as in vitro inhibition of platelet function occurs at plasma concentrations of nifedipine in excess of 50 uM, while the peak plasma concentration following a single 10 mg oral dose of nifedipine is only 0.2 uM. We have used the Haemostatometer, to assess the effect of nifedipine on haemostasis ex vivo. This instrument allows quantitative assessment of haemostasis by monitoring the pattern of haemostatic plug formation (HPF) in holes punched through polyethylene tubing through which non-anticoagulated blood flows under standard conditions (1,2). The pattern and speed of blood coagulation subsequent to HPF was measured as was the spontaneous thrombolysis time (STT) (taken as the time until expulsion of the haemostatic plug from heparinised blood). All values are for mean + SEM.Blood samples were taken from 10 healthy volunteers before and ninety minutes after a single 10 mg oral dose of nifedipine. Following nifedipine, the initial phase of the haemostatic reaction (HPF) was prolonged from 0.95 ± 0.12 min to 1.57 ± 0.14 min, (p< 0.01); clotting time was also increased from 13.1 ± 1.1 min to 20.7 ± 2.3 min, (p=0.013), and the STT fell from 48.0 ± 9.9 min to 27.5 ± 4.6 min (p=0.014).The increased bleeding time (HPF) provides evidence that a therapeutic dose of nifedipine evokes an anti-platelet effect. The prolongation of the clotting time seen in this study could be explained by,an effect of nifedipine on platelets and hence clotting. The mechanism of the enhanced spontaneous thrombolysis following nifedipine is not known.We suggest that the effect of nifedipine on haemostasis and thrombolysis may contribute to its therapeutic effect.(1) Gorog P and Kovacs I B. Haemostasis 16: 337-345, 1986.(2) Gorog P. Angiology 37: 99-105, 1986.

scholarly journals Effects of the Antifungals Voriconazole and Fluconazole on the Pharmacokinetics of S-(+)- and R-(−)-Ibuprofen

2006 ◽  
Vol 50 (6) ◽  
pp. 1967-1972 ◽  
Author(s):  
Ville-Veikko Hynninen ◽  
Klaus T. Olkkola ◽  
Kari Leino ◽  
Stefan Lundgren ◽  
Pertti J. Neuvonen ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Peak Plasma ◽  
Peak Plasma Concentration ◽  
Geometric Mean ◽  
Plasma Concentrations ◽  
Time Curve ◽  
Respective Control ◽  
Control Value ◽  
Racemic Ibuprofen ◽  
The Mean

ABSTRACT Our objective was to study the effects of the antifungals voriconazole and fluconazole on the pharmacokinetics of S-(+)- and R-(−)-ibuprofen. Twelve healthy male volunteers took a single oral dose of 400 mg racemic ibuprofen in a randomized order either alone, after ingestion of voriconazole at 400 mg twice daily on the first day and 200 mg twice daily on the second day, or after ingestion of fluconazole at 400 mg on the first day and 200 mg on the second day. Ibuprofen was ingested 1 h after administration of the last dose of voriconazole or fluconazole. Plasma concentrations of S-(+)- and R-(−)-ibuprofen were measured for up to 24 h. In the voriconazole phase, the mean area under the plasma concentration-time curve (AUC) of S-(+)-ibuprofen was 205% (P < 0.001) of the respective control value and the mean peak plasma concentration (C max) was 122% (P < 0.01) of the respective control value. The mean elimination half-life (t 1/2) was prolonged from 2.4 to 3.2 h (P < 0.01) by voriconazole. In the fluconazole phase, the mean AUC of S-(+)-ibuprofen was 183% of the control value (P < 0.001) and its mean C max was 116% of the control value (P < 0.05). The mean t 1/2 of S-(+)-ibuprofen was prolonged from 2.4 to 3.1 h (P < 0.05) by fluconazole. The geometric mean S-(+)-ibuprofen AUC ratios in the voriconazole and fluconazole phases were 2.01 (90% confidence interval [CI], 1.80 to 2.22) and 1.82 (90% CI, 1.72 to 1.91), respectively, i.e., above the bioequivalence acceptance upper limit of 1.25. Voriconazole and fluconazole had only weak effects on the pharmacokinetics of R-(−)-ibuprofen. In conclusion, voriconazole and fluconazole increased the levels of exposure to S-(+)-ibuprofen 2- and 1.8-fold, respectively. This was likely caused by inhibition of the cytochrome P450 2C9-mediated metabolism of S-(+)-ibuprofen. A reduction of the ibuprofen dosage should be considered when ibuprofen is coadministered with voriconazole or fluconazole, especially when the initial ibuprofen dose is high.

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