scholarly journals Induction of theophylline clearance by rifampin and rifabutin in healthy male volunteers.

1996 ◽  
Vol 40 (8) ◽  
pp. 1866-1869 ◽  
Author(s):  
J G Gillum ◽  
J M Sesler ◽  
V L Bruzzese ◽  
D S Israel ◽  
R E Polk
Keyword(s):  
Treatment Phase ◽  
Pharmacokinetic Parameters ◽  
Theophylline Clearance ◽  
Healthy Male ◽  
Time Curve ◽  
Concentration Time ◽  
Male Volunteers ◽  
Hepatic Microsomal Enzyme ◽  
The Mean ◽  
To Receive

Rifampin and rifabutin induce the metabolism of many drugs, which may result in subtherapeutic concentrations and failure of therapy. However, differences between rifabutin and rifampin in potency of induction, and the specific enzymes which are altered, are not clear. This study, involving 12 adult male volunteers, compared the effects of 14-day courses of rifampin and rifabutin on clearance of theophylline, a substrate for the hepatic microsomal enzyme CYP1A2. Subjects were given oral theophylline solution (5 mg/kg of body weight) on day 1 and then randomized to receive daily rifampin (300 mg) or rifabutin (300 mg) on days 3 to 16. Theophylline was readministered as described above on day 15. The first treatment sequence was followed by a 2-week washout period; subjects then received the alternative treatment. Theophylline concentrations were determined for 46 h after each dose, and pharmacokinetic parameters were determined. One subject developed flu-like symptoms while taking rifabutin and withdrew voluntarily. Results from the remaining 11 subjects are reported. Compared with the baseline, the mean area under the concentration-time curve (AUC) (+/- standard deviation) for theophylline declined significantly following rifampin treatment (from 140 +/- 37 to 100 +/- 24 micrograms . h/ml, P <0.001); there was no significant change following rifabutin treatment (136 +/- 48 to 128 +/- 45 micrograms.h/ml). Baseline theophylline AUCs before each treatment phase were not different. A comparison of equal doses of rifampin and rifabutin administered to healthy volunteers for 2 weeks indicates that induction of CYP1A2, as measured by theophylline clearance, is significantly less following rifabutin treatment than it is following rifampin treatment. However, the relative induction potency for other metabolic enzymes remains to be investigated.

scholarly journals Pharmacokinetics of Azithromycin Administered Alone and with Atovaquone in Human Immunodeficiency Virus-Infected Children

1999 ◽  
Vol 43 (6) ◽  
pp. 1516-1519 ◽  
Author(s):  
Leock Y. Ngo ◽  
Ram Yogev ◽  
Wayne M. Dankner ◽  
Walter T. Hughes ◽  
Sandra Burchett ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Steady State ◽  
Pharmacokinetic Parameters ◽  
Time Curve ◽  
Concentration Time ◽  
Significant Difference ◽  
Immunodeficiency Virus ◽  
The Mean ◽  
Clinically Significant ◽  
To Receive

ABSTRACT To evaluate if atovaquone (ATQ) interacts pharmacokinetically with azithromycin (AZ) in human immunodeficiency virus-infected children, 10 subjects (ages, 4 to 13 years) were randomized in a crossover study to receive AZ (5 mg/kg/day) alone (ALONE) or AZ (5 mg/kg/day) and ATQ (30 mg/kg/day) simultaneously (SIM) prior to receiving AZ and ATQ staggered by 12 h. Despite a lack of significant difference in the mean AZ pharmacokinetic parameters, the steady-state values of AZ’s area under the concentration-time curve from 0 to 24 h and maximum concentration in serum were consistently lower (n = 7 of 7) for the SIM regimen than they were for the ALONE regimen. A larger study will be required to determine if ATQ affects AZ pharmacokinetics and efficacy in a clinically significant manner.

Pharmacokinetics and metabolism of genaconazole, a potent antifungal drug, in men.

1996 ◽  
Vol 40 (1) ◽  
pp. 92-96 ◽  
Author(s):  
C Lin ◽  
H Kim ◽  
E Radwanski ◽  
M Affrime ◽  
M Brannan ◽  
...  
Keyword(s):  
Oral Dose ◽  
Single Oral Dose ◽  
Total Radioactivity ◽  
Healthy Male ◽  
Serum Samples ◽  
Time Curve ◽  
Concentration Time ◽  
Healthy Male Volunteers ◽  
Male Volunteers ◽  
The Mean

The pharmacokinetics of genaconazole, a racemic triazole antifungal agent comprising 50% RR and 50% SS enantiomers, were studied in 12 healthy male volunteers after a single oral dose of 200 mg. The serum samples were analyzed for the two enantiomers by using a chiral high-pressure liquid chromatography assay. The concentrations of the RR and SS enantiomers in serum were virtually identical. The mean values for the maximum concentrations in serum (Cmax) (1.7 micrograms/ml), times to Cmax (4.0 to 4.2 h), half-lives (83 h), and areas under the concentration-time curve from 0 h to infinity (195 to 199 micrograms.h/ml) were similar for the two enantiomers. The results showed that the pharmacokinetic profiles of the two enantiomers were similar after a single oral dosing of the racemate. The pharmacokinetics of the RR enantiomer were also evaluated in 12 healthy male volunteers after a single oral dose of 100 or 200 mg. The ratios of the Cmaxs and of the areas under the concentration-time curves from 0 h to infinity for the two doses were about 2, indicating a dose proportionality. In a separate study, six healthy male volunteers received a single oral dose of 50 mg of 14C-labeled genaconazole. The Cmax values for total radioactivity (14C) and intact genaconazole were virtually identical (0.6 micrograms/ml). The mean half-lives in serum were about 73 h for both total radioactivity and genaconazole. The amounts of total radioactivity excreted in the 0 to 240-h interval (representing approximately three half-lives) in urine and feces were 66.6 and 9.3% of the dose, respectively; 64.4% of the dose was excreted in urine as parent drug. There were no detectable metabolites in either serum or urine. The data demonstrate that genaconazole (racemate) is well absorbed, undergoes negligible biotransformation, and is slowly excreted, primarily in the urine.

scholarly journals Safety, toleration, and pharmacokinetics of intravenous azithromycin.

1996 ◽  
Vol 40 (11) ◽  
pp. 2577-2581 ◽  
Author(s):  
D R Luke ◽  
G Foulds ◽  
S F Cohen ◽  
B Levy
Keyword(s):  
Half Life ◽  
Active Drug ◽  
Slow Release ◽  
Volume Of Distribution ◽  
Pharmacokinetic Parameters ◽  
Time Curve ◽  
Concentration Time ◽  
Elimination Half ◽  
The Mean ◽  
Male Subjects

To date, the clinical pharmacology of large intravenous doses of azithromycin has not been described. In the present study, single 2-h intravenous infusions of 1, 2, and 4 g of azithromycin were administered to three parallel groups (in each group, six received active drug and two received placebo) of healthy male subjects. Toleration (assessed by scores of subject-administered visual analog scale tests spanning 0 [good] to 10 [poor]), safety, pharmacokinetics, and serum motilin levels were monitored for up to 240 h after the start of each intravenous infusion. Mean nausea scores of 0.0, 0.0, 1.0, and 0.5 and abdominal cramping scores of 0.0, 0.0, 0.4, and 0.4 for 12-h periods after doses of 0, 1, 2, and 4 g of azithromycin, respectively, suggested that azithromycin was well tolerated. Because of the standardized 1-mg/ml infusates, all subjects in the 4-g dosing group complained of an urgent need to urinate. There were no consistent trends in endogenous motilin levels throughout the study. The maximum concentration of azithromycin in serum (10 micrograms/ml after a 4-g dose) and the area under the concentration-time curve (82 micrograms.h/ml after a 4-g dose) were dose related. The mean pharmacokinetic parameters were an elimination half-life of 69 h, total systemic clearance of 10 ml/min/kg, and a volume of distribution at steady state of 33.3 liters/kg. The pharmacokinetic results suggest that the long half-life of azithromycin is due to extensive uptake and slow release of the drug from tissues rather than an inability to clear the drug. Single intravenous doses of up to 4 g of azithromycin in healthy subjects are generally well tolerated, and quantifiable concentrations may persist in serum for 10 days or more.

scholarly journals Pharmacokinetics of a Fluoronaphthyridone, Trovafloxacin (CP 99,219), in Infants and Children following Administration of a Single Intravenous Dose of Alatrofloxacin

2000 ◽  
Vol 44 (5) ◽  
pp. 1195-1199 ◽  
Author(s):  
John S. Bradley ◽  
Gregory L. Kearns ◽  
Michael D. Reed ◽  
Edmund V. Capparelli ◽  
John Vincent
Keyword(s):  
Volume Of Distribution ◽  
Intravenous Dose ◽  
Pharmacokinetic Parameters ◽  
Single Intravenous Dose ◽  
Average Standard Deviation ◽  
Time Curve ◽  
Concentration Time ◽  
Age Related ◽  
The Mean ◽  
In Infants And Children

ABSTRACT The pharmacokinetics of trovafloxacin following administration of a single intravenous dose of alatrofloxacin, equivalent to 4 mg of trovafloxacin per kg of body weight, were determined in 6 infants (ages 3 to 12 months) and 14 children (ages, 2 to 12 years). There was rapid conversion of alatrofloxacin to trovafloxacin, with an average ± standard deviation (SD) peak trovafloxacin concentration determined at the end of the infusion of 4.3 ± 1.4 μg/ml. The primary pharmacokinetic parameters (average ± SD) analyzed were volume of distribution at steady state (1.6 ± 0.6 liters/kg), clearance (151 ± 82 ml/h/kg), and half-life (9.8 ± 2.9 h). The drug was well tolerated by all children. There were no age-related differences in any of the pharmacokinetic parameters studied. Less than 5% of the administered dose was excreted in the urine over 24 h. On the basis of the mean area under the concentration-time curve of 30.5 ± 10.1 μg · h/ml and the susceptibility (≤0.5 μg/ml) of common pediatric bacterial pathogens to trovafloxacin, dosing of 4 mg/kg/day once or twice daily should be appropriate.

scholarly journals Assessment of the Effect of Mefloquine on Artesunate Pharmacokinetics in Healthy Male Volunteers

2006 ◽  
Vol 51 (3) ◽  
pp. 1099-1101 ◽  
Author(s):  
Timothy M. E. Davis ◽  
Michelle England ◽  
Anne-Marie Dunlop ◽  
Madhu Page-Sharp ◽  
Nathalie Cambon ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Active Metabolite ◽  
Healthy Male ◽  
Time Curve ◽  
Concentration Time ◽  
Healthy Male Volunteers ◽  
Male Volunteers

ABSTRACT The effect of mefloquine on artesunate pharmacokinetics was assessed in 20 volunteers given artesunate for 3 days, followed ≥21 days later by combination therapy for 3 days. The areas under the concentration-time curve from 0 h to infinity for dihydroartemisinin, the active metabolite of artesunate, were similar on day 3 of the two dosing periods (P = 0.12), implying no interaction.

scholarly journals Oral bioavailability and pharmacokinetics of ciprofloxacin in patients with AIDS.

1997 ◽  
Vol 41 (7) ◽  
pp. 1508-1511 ◽  
Author(s):  
R C Owens ◽  
K B Patel ◽  
M A Banevicius ◽  
R Quintiliani ◽  
C H Nightingale ◽  
...  
Keyword(s):  
Absolute Bioavailability ◽  
Pharmacokinetic Parameters ◽  
Crossover Fashion ◽  
Time Curve ◽  
Mean Values ◽  
Severe Diarrhea ◽  
Concentration Time ◽  
Infectious Gastroenteritis ◽  
Dosing Regimens ◽  
The Mean

Few reports on the effects of AIDS on the absorption of orally (p.o.) administered agents exist. To help fill this informational gap, we administered ciprofloxacin to 12 patients with AIDS by two dosing regimens (400 mg given intravenously [i.v.] and 500 mg given p.o. every 12 h) in a randomized, crossover fashion. Pharmacokinetic parameters were determined by noncompartmental methods. Mean values (+/- standard deviations [SD]) for p.o. ciprofloxacin were as follows: peak concentration of drug in serum (Cmax), 2.94 +/- 0.51 microg/ml; time to Cmax, 1.38 +/- 0.43 h; area under the concentration-time curve from 0 to 12 h (AUC(0-12)), 12.13 +/- 3.21 microg x h/ml; and half-life (t(1/2)), 3.86 +/- 0.48 h. Mean values (+/- SD) for i.v. ciprofloxacin were as follows: Cmax, 3.61 +/- 0.82 microg/ml; time to Cmax, 1.0 h; AUC(0-12), 11.92 +/- 2.92 microg x h/ml; and t(1/2), 3.98 +/- 0.94 h. The mean percent absolute bioavailability for ciprofloxacin was calculated to be 82% +/- 13%, similar to the value for healthy volunteers. We conclude that ciprofloxacin when administered p.o. to patients with AIDS is well absorbed, as evidenced by excellent bioavailability and is not affected by gastrointestinal changes in the absence of infectious gastroenteritis and severe diarrhea.

scholarly journals Pharmacokinetics and Inflammatory Fluid Penetration of Intravenous Daptomycin in Volunteers

2002 ◽  
Vol 46 (1) ◽  
pp. 31-33 ◽  
Author(s):  
R. Wise ◽  
T. Gee ◽  
J. M. Andrews ◽  
B. Dvorchik ◽  
G. Marshall
Keyword(s):  
Body Weight ◽  
Standard Deviation ◽  
Total Drug ◽  
Healthy Male ◽  
Urinary Recovery ◽  
Time Curve ◽  
Concentration Time ◽  
Elimination Half ◽  
The Mean ◽  
Fluid Penetration

ABSTRACT The lipopeptide antimicrobial daptomycin was administered intravenously at a dose of 4 mg/kg of body weight to seven healthy male volunteers. The concentrations of daptomycin in plasma, cantharidin-induced inflammatory fluid, and urine were measured by a microbiological assay. The mean ± standard deviation peak concentrations in plasma and inflammatory fluid were 77.5 ± 8.3 and 27.6 ± 9.5 μg/ml, respectively; the mean terminal elimination half-lives were 7.74 and 13.2 h, respectively. The overall penetration of total drug into the inflammatory fluid (measured by ratio of the area under the concentration-time curve from 0 to 24 h for inflammatory fluid compared with that for plasma) was 68.4%. The mean urinary recovery over 24 h was 59.7%.

Effect of Terbinafine on Theophylline Pharmacokinetics in Healthy Volunteers

1998 ◽  
Vol 42 (3) ◽  
pp. 695-697 ◽  
Author(s):  
Eric F. Trépanier ◽  
Anne N. Nafziger ◽  
Guy W. Amsden
Keyword(s):  
Healthy Volunteers ◽  
Multiple Dose ◽  
Treatment Phase ◽  
Pharmacokinetic Parameters ◽  
Noncompartmental Analysis ◽  
Open Label ◽  
Time Curve ◽  
Blood Samples ◽  
Concentration Time ◽  
Randomized Crossover Study

ABSTRACT Twelve healthy volunteers were enrolled in an open-label, randomized, crossover study. Subjects received single doses of theophylline (5 mg/kg) with and without multiple-dose terbinafine, and 11 blood samples were collected over 24 h. The study phases were separated by a 4-week washout period. Theophylline serum data were modeled via noncompartmental analysis. When the control phase (i.e., no terbinafine) was compared to the treatment phase (terbinafine), theophylline exposure (the area under the serum concentration-time curve from time zero to infinity) increased by 16% (P= 0.03), oral clearance decreased by 14% (P = 0.04), and half-life increased by 24% (P = 0.002). No significant changes in other theophylline pharmacokinetic parameters were evident.

scholarly journals Effects of FMO3 Polymorphisms on Pharmacokinetics of Sulindac in Chinese Healthy Male Volunteers

2017 ◽  
Vol 2017 ◽  
pp. 1-7 ◽  
Author(s):  
Yong-Jun Tang ◽  
Kai Hu ◽  
Wei-Hua Huang ◽  
Chong-Zhi Wang ◽  
Zhi Liu ◽  
...  
Keyword(s):  
Plasma Concentrations ◽  
Pharmacokinetic Parameters ◽  
Healthy Male ◽  
Mean Values ◽  
Healthy Male Volunteers ◽  
Male Volunteers ◽  
Pcr Rflp ◽  
Hardy Weinberg Equilibrium ◽  
Sulindac Sulfide ◽  
The Mean

Sulindac is a nonsteroidal anti-inflammatory drug, which is clinically used for the ailments of various inflammations. This study investigated the allele frequencies of FMO3 E158K and E308G and evaluated the influences of these two genetic polymorphisms on the pharmacokinetics of sulindac and its metabolites in Chinese healthy male volunteers. Eight FMO3 wild-type (FMO3 HHDD) subjects and seven FMO3 homozygotes E158K and E308G mutant (FMO3 hhdd) subjects were recruited from 247 healthy male volunteers genotyped by PCR-RFLP method. The plasma concentrations of sulindac, sulindac sulfide, and sulindac sulfone were determined by UPLC, while the pharmacokinetic parameters of the two different FMO3 genotypes were compared with each other. The frequencies of FMO3 E158K and E308G were 20.3% and 20.1%, respectively, which were in line with Hardy-Weinberg equilibrium (D′ = 0.977, r2 = 0.944). The mean values of Cmax, AUC0–24, and AUC0–∞ of sulindac were significantly higher in FMO3 hhdd group than those of FMO3 HHDD group (P<0.05), while the pharmacokinetic parameters except Tmax of sulindac sulfide and sulindac sulfone showed no statistical difference between the two groups. The two FMO3 mutants were in close linkage disequilibrium and might play an important role in the pharmacokinetics of sulindac in Chinese healthy male volunteers.

Liquid Chromatography-Tandem Mass Spectrometry Method for Ticagrelor and its Active Metabolite Determination in Human Plasma: Application to a Pharmacokinetic Study

2020 ◽  
Vol 16 (5) ◽  
pp. 602-608
Author(s):  
Niloufar Marsousi ◽  
Serge Rudaz ◽  
Jules A. Desmeules ◽  
Youssef Daali
Keyword(s):  
Clinical Trial ◽  
Formic Acid ◽  
Human Plasma ◽  
Active Metabolite ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Studies ◽  
Healthy Male ◽  
Coronary Syndrome ◽  
Healthy Male Volunteers ◽  
Male Volunteers

Background: Ticagrelor is a highly recommended new antiplatelet agent for the treatment of patients with acute coronary syndrome at moderate or high ischemic risk. There is a real need for rapid and accurate analytical methods for ticagrelor determination in biological fluids for pharmacokinetic studies. In this study, a sensitive and specific LC-MS method was developed and validated for quantification of ticagrelor and its Active Metabolite (AM) in human plasma over expected clinical concentrations. Methods: Samples were handled by Liquid-Liquid Extraction (LLE). A linear gradient was applied with a mobile phase composed of formic acid 0.1% and acetonitrile with 0.1% of formic acid using a C18 reversed-phase column. MS spectra were obtained by electrospray ionization in negative mode and optimized at 521.4→360.9 m/z, 477.2→361.2 m/z and 528.1→367.9 m/z transitions for ticagrelor, AM and ticagrelor-d7, respectively. Results: This method allowed rapid elution, in less than 4 minutes, and quantification of concentrations as low as 2 ng/mL for ticagrelor and 1 ng/mL for AM using only 100 μL of human plasma. LLE using hexane/ethyl acetate (50/50) was an optimal compromise in terms of extraction recovery and endogenous compounds interference. Trueness values of 87.8% and 89.5% and precisions of 84.1% and 93.8% were obtained for ticagrelor and AM, respectively. Finally, the usefulness of the method was assessed in a clinical trial where a single 180 mg ticagrelor was orally administered to healthy male volunteers. Pharmacokinetic parameters of ticagrelor and its active metabolite were successfully determined. Conclusion: A sensitive and specific quantification LC-MS-MS method was developed and validated for ticagrelor and its active metabolite determination in human plasma. The method was successfully applied to a clinical trial where a single ticagrelor 180 mg dose was orally administered to healthy male volunteers. The described method allows quantification of concentrations as low as 2 ng/mL of ticagrelor and 1 ng/mL of the metabolite using only 100 μL of plasma.

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