scholarly journals Analysis of the Pharmacokinetic Interaction between Cephalexin and Quinapril by a Nonlinear Mixed-Effect Model

1998 ◽  
Vol 42 (6) ◽  
pp. 1463-1469 ◽  
Author(s):  
C. Padoin ◽  
M. Tod ◽  
G. Perret ◽  
O. Petitjean
Keyword(s):  
Competitive Inhibition ◽  
Pharmacokinetic Interaction ◽  
Angiotensin Converting Enzyme Inhibitors ◽  
Oral Route ◽  
Elimination Kinetics ◽  
Time Curve ◽  
Converting Enzyme Inhibitors ◽  
Mixed Effect ◽  
Nonlinear Mixed Effect ◽  
The Mean

ABSTRACT Oligopeptidic drugs such as β-lactams and angiotensin-converting enzyme inhibitors share the same carriers in humans and animals, which results in possible pharmacokinetic interactions. To model such interactions, the effects of quinapril on cephalexin pharmacokinetics were investigated in rats. Blood cephalexin concentrations were measured by liquid chromatography, and the data were analyzed by a noncompartmental method and by fitting a bicompartmental model by a nonlinear mixed-effect modeling approach. Five groups of eight rats were examined. In the first three groups, cephalexin elimination kinetics after intra-arterial administration alone or in combination with quinapril given by the parenteral or the oral route were studied, and the occurrence of a pharmacokinetic interaction was not revealed. The absence of an effect of quinapril on cephalexin elimination after parenteral administration might be explained either by the higher affinity of cephalexin for the renal anionic transport system than that of quinapril or by the much higher concentrations of cephalexin than those of quinapril. In the last two groups, cephalexin was administered by the oral route alone or in combination with quinapril. The mean area under the concentration-time curve (AUC) for cephalexin was increased by ca. 30% by coadministration of quinapril (40.1 versus 31.4 mg · h/liter;P = 0.04). The mean elimination clearance of cephalexin was significantly decreased by quinapril, from 0.81 to 0.64 liter/h/kg of body weight (P < 0.05), probably by competitive inhibition of cephalexin secretion at the tubular level. The mean absorption rate constant of cephalexin was significantly lowered by quinapril (from 0.249 to 0.177 h−1;P < 0.01), without modification of the extent of absorption (89%). This pharmacokinetic interaction could be explained by competitive inhibition of cephalexin active transport by quinapril at the intestinal level.

Pharmacokinetic interaction between cefdinir and two angiotensin-converting enzyme inhibitors in rats.

1996 ◽  
Vol 40 (4) ◽  
pp. 979-982 ◽  
Author(s):  
A Jacolot ◽  
M Tod ◽  
O Petitjean
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Enzyme Inhibitors ◽  
Enzyme Inhibitor ◽  
Pharmacokinetic Interaction ◽  
Angiotensin Converting Enzyme Inhibitors ◽  
Converting Enzyme ◽  
Time Curve ◽  
Converting Enzyme Inhibitors ◽  
Group 2 ◽  
Group 1

The pharmacokinetic interaction between cefdinir and an angiotensin-converting enzyme inhibitor (captopril or quinapril) was investigated in rats. The linearity of cefdinir pharmacokinetics was demonstrated in three groups of rats receiving 10, 20, or 40 mg of cefdinir per kg of body weight intravenously. Then, three other groups of rats were established as follows: group 1 (n = 5) received cefdinir (10 mg/kg) intravenously, and 12 blood samples per rat were drawn between 0 and 8 h after injection of the dose; group 2 (n = 5) was treated in the same way as group 1, but captopril (0.8 mg/kg) was coadministered by intraintestinal injection into all animals; group 3 (n = 6) was treated in the same way as group 2, but quinapril (0.8 mg/kg) replaced captopril. Plasma cefdinir concentrations were measured by liquid chromatography, and the data were analyzed by a noncompartmental method. Finally, three groups of four or five rats each were set up as described above, but the cefdinir dose was 20 mg/kg and the animals were sacrificed 1 h after drug injection to collect blood to determine the unbound cefdinir fraction (fu) by ultrafiltration. The angiotensin-converting enzyme inhibitors increased the mean cefdinir area under the concentration-time curve up to 8 h by a factor of 1.8 (captopril; P < 0.05) and a factor of 3.5 (quinapril; P < 0.05). With captopril, mean cefdinir clearance was decreased by a factor of 2, and the volume of distribution increased by the same factor, while the fu increased from 15.4% +/- 3.0% (cefdinir alone) to 22.8% +/- 10.9% (cefdinir plus captopril). Captopril increased the cefdinir half-life from 0.62 +/- 0.17 to 2.92 +/- 0.95 h. With quinapril, the interaction was so strong that no elimination phase was detectable in four of the six rats, and therefore, no pharmacokinetic parameter values other than the cefdinir fu could be calculated; the cefdinir fu increased to 25.1% +/- 11.1%. It is concluded that captopril and quinapril (and/or their metabolites) have a major impact on the disposition of cefdinir in rats, probably by competition at the plasma protein-binding level and at the tubular anionic carrier level. This latter mechanism should also be relevant in humans.

Influence of Renal Failure on Ciprofloxacin Pharmacokinetics in Rats

1998 ◽  
Vol 42 (2) ◽  
pp. 289-292 ◽  
Author(s):  
B. Nouaille-Degorce ◽  
C. Veau ◽  
S. Dautrey ◽  
M. Tod ◽  
D. Laouari ◽  
...  
Keyword(s):  
Renal Failure ◽  
Intestinal Secretion ◽  
Parenteral Administration ◽  
Compensatory Mechanisms ◽  
Time Curve ◽  
Mixed Effect ◽  
Nonlinear Mixed Effect Model ◽  
Nonlinear Mixed Effect ◽  
Effect Model ◽  
Elimination Half

ABSTRACT Ciprofloxacin pharmacokinetics have been shown to be modified in patients with renal failure (e.g., the intestinal secretion of ciprofloxacin is increased). This study investigated the influence of renal failure on the pharmacokinetics of ciprofloxacin following oral and parenteral administration to rats of a dose of 50 mg/kg of body weight. After parenteral administration, only renal clearance (CLR) was reduced in nephrectomized rats (5.3 ± 1.4 versus 17.8 ± 4.7 ml/min/kg, P< 0.01, nephrectomized versus control rats). However, nonrenal clearance was increased in nephrectomized rats (32 ± 4 versus 15 ± 5 ml/min/kg, P < 0.01, nephrectomized versus control rats), suggesting compensatory mechanisms for reduced renal function. After oral administration, apparent total clearance and CLR were reduced (P < 0.01) in nephrectomized rats (117 ± 25 and 6.8 ± 4.4 ml/min/kg, respectively) compared with the values for control rats (185 ± 9 and 22.6 ± 5.3 ml/min/kg, respectively) and the area under the concentration-time curve was higher (P < 0.01) for nephrectomized rats (436.3 ± 90.5 mg · min/liter) than for control rats (271.3 ± 14.3 mg · min/liter). Terminal elimination half lives in the two groups remained constant after oral and parenteral administration. These results suggest an increased bioavailability of ciprofloxacin in nephrectomized rats, which was confirmed by a nonlinear mixed-effect model.

scholarly journals Population Pharmacokinetics and Pharmacodynamic Target Attainment of Isavuconazole against Aspergillus fumigatus and Aspergillus flavus in Adult Patients with Invasive Fungal Diseases: Should Therapeutic Drug Monitoring for Isavuconazole Be Considered as Mandatory as for the Other Mold-Active Azoles?

Pharmaceutics ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2099
Author(s):  
Pier Giorgio Cojutti ◽  
Alessia Carnelutti ◽  
Davide Lazzarotto ◽  
Emanuela Sozio ◽  
Anna Candoni ◽  
...  
Keyword(s):  
Invasive Pulmonary Aspergillosis ◽  
Invasive Fungal Disease ◽  
The Other ◽  
Therapeutic Drug ◽  
Population Pharmacokinetic ◽  
Target Attainment ◽  
Time Curve ◽  
Mixed Effect ◽  
Nonlinear Mixed Effect ◽  
Pharmacodynamic Analysis

Isavuconazole is a newer broad-spectrum triazole approved for the treatment of invasive fungal disease. The objective of this study was to conduct a population pharmacokinetic and pharmacodynamic analysis of isavuconazole in a retrospective cohort of hospitalized patients. A nonlinear mixed-effect approach with Monte Carlo simulations was conducted to assess the probability of target attainment (PTA) of an area under the concentration–time curve (AUC24 h)/minimum inhibitory concentration (MIC) ratio of 33.4 (defined as efficacy threshold against A. fumigatus and A. flavus) associated with a maintenance dose (MD) of 100, 200 and 300 mg daily after loading. The cumulative fraction of response (CFR) against the EUCAST MIC distributions of A. fumigatus and A. flavus was calculated as well. The proportion of trough concentrations (Ctrough) exceeding a defined threshold of toxicity (>5.13 mg/L) was estimated. A total of 50 patients, with a median age of 61.5 years, provided 199 plasma isavuconazole concentrations. Invasive pulmonary aspergillosis was the prevalent type of infection and accounted for 80% (40/50) of cases. No clinical covariates were retained by the model. With the standard MD of 200 mg daily, CFRs were always ≥90% during the first two months of treatment. The risk of Ctrough < 1.0 mg/L was around 1%, and that of Ctrough > 5.13 mg/L was 27.7 and 39.2% at 28 and 60 days, respectively, due to isavuconazole accumulation over time. Our findings suggest that TDM for isavuconazole should not be considered as mandatory as for the other mold-active azoles voriconazole and posaconazole.

scholarly journals Pharmacokinetic interaction between itraconazole and ceftriaxone in Yucatan miniature pigs.

1997 ◽  
Vol 41 (9) ◽  
pp. 2029-2032 ◽  
Author(s):  
A Cavalier ◽  
D Levêque ◽  
J D Peter ◽  
J Salmon ◽  
H Elkhaïli ◽  
...  
Keyword(s):  
Antimicrobial Agents ◽  
Efflux Pump ◽  
Pharmacokinetic Interaction ◽  
Time Curve ◽  
Miniature Pigs ◽  
Concentration Time ◽  
P Glycoprotein ◽  
Chronic Model ◽  
The Mean

Since ceftriaxone and itraconazole are highly protein bound, are excreted via a biliary pathway, and are in vitro modulators of the efflux pump P glycoprotein, a pharmacokinetic interaction between these antimicrobial agents can be hypothesized. Therefore, we evaluated the pharmacokinetics of itraconazole and ceftriaxone alone and in combination in a chronic model of catheterized miniature pigs. Itraconazole does not influence ceftriaxone kinetic behavior. The mean areas under the concentration-time curve (AUC) were 152.2 microg x h/ml (standard deviation [SD], 22.5) and 129.2 microg x h/ml (SD, 41.2) and the terminal half-lives were 1.1 h (SD, 0.3) and 0.9 h (SD, 0.2) when ceftriaxone was given alone and combined with itraconazole, respectively. Regarding itraconazole kinetics, ceftriaxone was shown to alter the disposition of the triazole. Contrary to what was expected, the AUC (from 0 to 8 h) decreased from 139.3 ng h/ml with itraconazole alone to 122.7 ng h/ml with itraconazole and ceftriaxone combined in pig 1, from 398.5 to 315.7 ng x h/ml in pig 2, and from 979.6 to 716.6 ng x h/ml in pig 3 (P of <0.01 by analysis of variance).

scholarly journals Pharmacokinetic Interaction between Voriconazole and Methadone at Steady State in Patients on Methadone Therapy

2006 ◽  
Vol 51 (1) ◽  
pp. 110-118 ◽  
Author(s):  
Ping Liu ◽  
Grover Foster ◽  
Robert LaBadie ◽  
Eugene Somoza ◽  
Amarnath Sharma
Keyword(s):  
Steady State ◽  
Safety Data ◽  
Pharmacokinetic Interaction ◽  
Tolerability Profile ◽  
Time Curve ◽  
Parallel Group ◽  
Male Patients ◽  
The Mean ◽  
Methadone Patients ◽  
Pharmacologically Active

ABSTRACT This trial was aimed to estimate the pharmacokinetic interaction between voriconazole and methadone at steady state in male patients on methadone therapy and to characterize the safety and tolerability profile during the coadministration. Twenty-three patients on individualized methadone therapy (30 to 100 mg once daily) were enrolled into this randomized, patient- and investigator-blind, placebo-controlled, parallel-group study. Methadone pharmacokinetic samples were collected from patients receiving methadone alone as the baseline before they were randomized to coadminister either 200 mg voriconazole twice daily (BID) (400-mg BID loading doses on the first day) (n = 16) or matching placebo (n = 7) for the next 5 days. Pharmacokinetic samples for methadone and voriconazole were collected on the last day of voriconazole dosing. The safety data were collected throughout the study. Voriconazole increased the steady-state exposure of pharmacologically active enantiomer (R)-methadone: the mean area under the concentration-time curve from 0 to 24 h (AUC0-24) was increased by 47.2% (90% confidence intervals [CI]: 37.7%, 57.4%), and the mean peak concentration (C max) was increased by 30.7% (90% CI: 22.2%, 39.8%). The magnitude of increase in (S)-methadone exposure was greater than that of (R)-methadone: the AUC0-24 was increased by 103.4% (90% CI: 85.0%, 123.6%), and the C max was increased by 65.4% (90% CI: 52.6%, 79.2%). Methadone appeared to have no effect on the steady-state voriconazole pharmacokinetics compared to the historical data for voriconazole alone. Methadone patients receiving voriconazole showed no signs or symptoms of significant opioid withdrawal or overdose. Coadministration of 200 mg voriconazole BID with methadone was generally safe and well tolerated. Nevertheless, caution should be exercised when voriconazole is coadministered with methadone due to the increase in (R)-methadone exposure, which in turn may require a dose reduction of methadone.

Complex Competitive and Non-Competitive Inhibition of Rat Lung Angiotensin-Converting Enzyme by Inhibitors Containing Thiol Groups: Captopril and SA 446

1981 ◽  
Vol 61 (s7) ◽  
pp. 277s-280s ◽  
Author(s):  
F. A. O. Mendelsohn ◽  
J. Csicsmann ◽  
J. S. Hutchinson
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Competitive Inhibition ◽  
Weighted Least Squares ◽  
Angiotensin Converting Enzyme Inhibitors ◽  
Converting Enzyme ◽  
Rat Lung ◽  
Thiol Groups ◽  
Converting Enzyme Inhibitors ◽  
Competitive Pattern

1. The kinetics of the inhibitory action of four different angiotensin-converting enzyme inhibitors was evaluated in vitro with rat lung enzyme and the substrate hippuryl-histidyl-leucine. 2. Enzyme velocity against substrate concentration curves were fitted directly to hyperbolae by a weighted least squares iterative method to obtain apparent values of Km, Vmax. and K/V at each concentration of inhibitor. 3. The inhibitory constants K1 and Kí were obtained by weighted linear regressions of K/V against i and 1/V against i respectively. 4. Teprotide was the least potent inhibitor with a K1 of near 20 nmol/l whereas captopril (SQ 14 225) and SA 446 were both approximately 10 times and MK 421 approximately 20 times more potent. 5. Two inhibitors which lacked thiol groups [teprotide or SQ 20 881 and N-(1-S-1-carboxy-3-phenylpropyl)-l-Ala-l-Pro or MK 421] produced a purely competitive pattern of inhibition with increased apparent Km but no change in apparent Vmax. 6. Two inhibitors containing thiol groups [captopril or SQ 14 225 and 2-(2′-hydroxyphenyl)-3-(3-mercaptopropanoyl)-4-thiazolidine carboxylic acid or SA 446] both produced a mixed competitive and non-competitive pattern of inhibition with increased apparent Km and decreased Vmax. 7. It is possible that thiol-containing inhibitors might produce non-competitive inhibition of converting enzyme by forming strong bonds with zinc near the active site of the enzyme.

scholarly journals Zidovudine, trimethoprim, and dapsone pharmacokinetic interactions in patients with human immunodeficiency virus infection.

1996 ◽  
Vol 40 (5) ◽  
pp. 1231-1236 ◽  
Author(s):  
B L Lee ◽  
S Safrin ◽  
V Makrides ◽  
J G Gambertoglio
Keyword(s):  
Human Immunodeficiency Virus ◽  
Pneumocystis Carinii ◽  
Pharmacokinetic Interaction ◽  
Urinary Recovery ◽  
Time Curve ◽  
Concentration Time ◽  
Pharmacokinetic Interactions ◽  
Immunodeficiency Virus ◽  
Blood And Urine Samples ◽  
The Mean

Zidovudine is widely prescribed for the treatment of human immunodeficiency virus (HIV) infection. Trimethoprim and dapsone are commonly used in the management of Pneumocystis carinii pneumonia in HIV-infected patients. To examine the pharmacokinetic interactions among these drugs, eight HIV-infected patients (26 to 43 years old) with a mean CD4 count of 524.4 +/- 405.7 cells per mm3 received zidovudine (200 mg), trimethoprim (200 mg), and dapsone (100 mg) as single agents and in two- and three-drug combinations. Blood and urine samples were collected at a specified time and analyzed for zidovudine, zidovudine-glucuronide, trimethoprim, dapsone, and monoacetyl-dapsone concentrations under single-dose and steady-state conditions. Zidovudine did not influence the pharmacokinetic disposition of dapsone or trimethoprim. Dapsone had no effect on the pharmacokinetic disposition of zidovudine. Trimethoprim significantly decreased the renal clearance of zidovudine by 58% (5.0 +/- 1.8 versus 2.1 +/- 0.5 ml/min/kg of body weight [P < 0.05]). There was a concurrent 54% decrease in the mean urinary recovery of zidovudine (11.7 +/- 3.5 versus 5.4 +/- 3.0 [P < 0.05]), and the metabolic ratio was decreased by 78% (0.32 +/- 0.4 versus 0.07 +/- 0.05 [P < 0.05]). The mean area under the concentration-time curve from 0 to 6 h of the zidovudine-glucuronide/ zidovudine ratio was unchanged. We conclude that zidovudine, trimethoprim, and dapsone can be coadministered to patients with AIDS without significant pharmacokinetic interaction. However, in AIDS patients with liver impairment and impaired glucuronidation, doses of zidovudine may need to be decreased.

scholarly journals Association of Inpatient Use of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers With Mortality Among Patients With Hypertension Hospitalized With COVID-19

2020 ◽  
Vol 126 (12) ◽  
pp. 1671-1681 ◽  
Author(s):  
Peng Zhang ◽  
Lihua Zhu ◽  
Jingjing Cai ◽  
Fang Lei ◽  
Juan-Juan Qin ◽  
...  
Keyword(s):  
Enzyme Inhibitors ◽  
Cox Model ◽  
Angiotensin Converting Enzyme Inhibitors ◽  
Hazard Ratio ◽  
Adjusted Hazard Ratio ◽  
Angiotensin Ii Receptor ◽  
Converting Enzyme Inhibitors ◽  
Mixed Effect ◽  
All Cause Mortality ◽  
Receptor Blockers

Rationale: Use of ACEIs (angiotensin-converting enzyme inhibitors) and ARBs (angiotensin II receptor blockers) is a major concern for clinicians treating coronavirus disease 2019 (COVID-19) in patients with hypertension. Objective: To determine the association between in-hospital use of ACEI/ARB and all-cause mortality in patients with hypertension and hospitalized due to COVID-19. Methods and Results: This retrospective, multi-center study included 1128 adult patients with hypertension diagnosed with COVID-19, including 188 taking ACEI/ARB (ACEI/ARB group; median age 64 [interquartile range, 55–68] years; 53.2% men) and 940 without using ACEI/ARB (non-ACEI/ARB group; median age 64 [interquartile range 57–69]; 53.5% men), who were admitted to 9 hospitals in Hubei Province, China from December 31, 2019 to February 20, 2020. In mixed-effect Cox model treating site as a random effect, after adjusting for age, gender, comorbidities, and in-hospital medications, the detected risk for all-cause mortality was lower in the ACEI/ARB group versus the non-ACEI/ARB group (adjusted hazard ratio, 0.42 [95% CI, 0.19–0.92]; P =0.03). In a propensity score-matched analysis followed by adjusting imbalanced variables in mixed-effect Cox model, the results consistently demonstrated lower risk of COVID-19 mortality in patients who received ACEI/ARB versus those who did not receive ACEI/ARB (adjusted hazard ratio, 0.37 [95% CI, 0.15–0.89]; P =0.03). Further subgroup propensity score-matched analysis indicated that, compared with use of other antihypertensive drugs, ACEI/ARB was also associated with decreased mortality (adjusted hazard ratio, 0.30 [95% CI, 0.12–0.70]; P =0.01) in patients with COVID-19 and coexisting hypertension. Conclusions: Among hospitalized patients with COVID-19 and coexisting hypertension, inpatient use of ACEI/ARB was associated with lower risk of all-cause mortality compared with ACEI/ARB nonusers. While study interpretation needs to consider the potential for residual confounders, it is unlikely that in-hospital use of ACEI/ARB was associated with an increased mortality risk.

scholarly journals Incidence and determinants of hyperkalemia among heart failure patients who used spironolactone

2021 ◽  
Author(s):  
Majed Nahari ◽  
Anas Aldawsari ◽  
Zuhair Alqahtani ◽  
Meshary Almeshary
Keyword(s):  
Risk Factors ◽  
Heart Failure ◽  
Beta Blockers ◽  
Retrospective Chart Review ◽  
Angiotensin Converting Enzyme Inhibitors ◽  
Data Sampling ◽  
Angiotensin Ii Receptor ◽  
Converting Enzyme Inhibitors ◽  
Heart Failure Patients ◽  
The Mean

Abstract Background Potassium balance in heart failure is affected by many factors including neurohormonal mechanisms and drugs used in its management. Renin–angiotensin–aldosterone system inhibitor therapies are part of heart failure therapy and have been associated with increase the risk of hyperkalemia. Currently, there are limited data on the prevalence and risk factors of hyperkalemia in heart failure patients who received spironolactone as an add-on to standard therapy which include Angiotensin-Converting Enzyme Inhibitors (ACEIs) or Angiotensin II receptor blockers (ARBs). The objective of this study is to identify Incidence and determine of hyperkalemia risk factors among heart failure patients who have been using spironolactone. Methods This is a retrospective chart review, from March 1, 2016 to March 31, 2019 conducted at King Abdulaziz Medical City-Riyadh. All heart failure patients with age more than 18 year who are using spironolactone were included and we excluded if they had any of the following criteria: (1) end stage renal disease on dialysis; (2) cancer; (3) history of hyperkalemia. A data collection sheet was used to collect demographics (e.g., age, gender, weight, ejection fraction, and baseline potassium), comorbidities (e.g., chronic kidney disease, and diabetes), visit history (dose of spironolactone, hyperkalemia incidence, time to the event, medication that was patient on include (ACEI, ARB, digoxin, furosemide, beta-blockers, and potassium supplements), average potassium level, average creatinine, and average BNP). An Excel-based tool (Microsoft® Excel; Version 2018) was used for systematic data sampling and analysis. The study was approved by Institutional Review Board. Results A total of 349 patients met the inclusion criteria. 43% of patients were men while 57% were women. The mean age of patients was 64.87 ± 14.02 years. The mean baseline of potassium before start spironolactone were 4.34 ± 3.45 mmol/L. Hyperkalemia were assessed with different dose of spironolactone (12.5 mg, 25 mg, 50 mg). 161 patients were received 12.5 mg spironolactone, 40% of those patients who had incidence of hyperkalemia. 62% of those who developed hyperkalemia were on ACEI, 28% on ARB, 14% on potassium supplements. 263 patients were received 25 mg spironolactone, 47% of patients had incidence of hyperkalemia. 49% of those who developed hyperkalemia were on ACEI, 31% on ARB, and 22% on potassium supplements. 17 patients were received 50 mg spironolactone, 53% of patients had incidence of hyperkalemia. 44% of those who developed hyperkalemia were on ACEI, 22% on ARB, and 22% on potassium supplements. Conclusion Our study showed that half of heart failure patients who used spironolactone developed hyperkalemia. The majority of patients who developed hyperkalemia were either on ACEIs or ARBs. Spironolactone dosing of 50 mg was associated with highest incidence of hyperkalemia. Further study with a larger sample size is required to clarify and confirm our study findings.

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