Pharmacokinetics of intramuscularly administered aminosidine in healthy subjects.

Aminosidine is an older, broad-spectrum aminoglycoside antibiotic that has been shown to be effective in in vitro and animal models against multiple-drug-resistant tuberculosis and the Mycobacterium avium complex. The objective of this randomized, parallel trial was to characterize the single-dose pharmacokinetics of aminosidine sulfate in healthy subjects (eight males, eight females). Sixteen adults (mean [+/- standard deviation] age, 27.6 +/- 5.6 years) were randomly allocated to receive a single, intramuscular aminosidine sulfate injection at a dose of 12 or 15 mg/kg of body weight. Serial plasma and urine samples were collected over a 24-h period and used to determine aminosidine concentrations by high-performance liquid chromatographic assay. A one-compartment model with first-order input, first-order output, and a lag time (Tlag) and with a weighting factor of 1/y2 best described the data. Compartmental and noncompartmental pharmacokinetic parameters were estimated with the microcomputer program WinNonlin. One subject was not included (15-mg/kg group) because of the lack of sampling time data. On average, subjects attained peak concentrations of 22.4 +/- 3.2 microg/ml at 1.34 +/- 0.45 h. All subjects had plasma aminosidine concentrations below 2 microg/ml at 12 h, and all but two subjects (one in each dosing group) had undetectable plasma aminosidine concentrations at 24 h. The dose-adjusted area under the concentration-time curve from 0 h to infinity of aminosidine was identical for the 12- and 15-mg/kg groups (9.29 +/- 1.5 versus 9.29 +/- 2.2 microg x h/ml per mg/kg; P = 0.998). Similarly, no significant differences (P > 0.05) were observed between dosing groups for peak aminosidine concentration in plasma, time to peak aminosidine concentration in plasma, Tlag, apparent clearance, renal clearance, elimination rate constant, and elimination half-life. A significant difference was observed for the volume of distribution (0.35 versus 0.41 liters/kg; P = 0.037) between the 12 and 15 mg/kg dosing groups. Now that comparable pharmacokinetic profiles between dosing groups have been demonstrated, therapeutic equivalency testing via in vitro pharmacokinetic and pharmacodynamic modelling and randomized clinical trials in humans should be conducted.

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Effects of Silymarin on the In Vivo Pharmacokinetics of Simvastatin and Its Active Metabolite in Rats

Molecules ◽

10.3390/molecules24091666 ◽

2019 ◽

Vol 24 (9) ◽

pp. 1666

Author(s):

Ying Li ◽

Yin Wu ◽

Ya-Jing Li ◽

Lu Meng ◽

Cong-Yang Ding ◽

...

Keyword(s):

Active Metabolite ◽

Compartmental Model ◽

Elimination Rate ◽

Pharmacokinetic Parameters ◽

Time Curve ◽

Simultaneous Quantification ◽

Concentration Time ◽

Significant Difference ◽

In Vivo Pharmacokinetics

Herein, the effect of silymarin pretreatment on the pharmacokinetics of simvastatin in rats was evaluated. To ensure the accuracy of the results, a rapid and sensitive UPLC–MS/MS method was established for simultaneous quantification of simvastatin (SV) and its active metabolite simvastatin acid (SVA). This method was applied for studying the pharmacokinetic interactions in rats after oral co-administration of silymarin (45 mg/kg) and different concentrations of SV. The major pharmacokinetic parameters, including Cmax, tmax, t1/2, mean residence time (MRT), elimination rate constant (λz) and area under the concentration-time curve (AUC0–12h), were calculated using the non-compartmental model. The results showed that the co-administration of silymarin and SV significantly increased the Cmax and AUC0–12h of SVA compared with SV alone, while there was no significant difference with regards to Tmax and t1/2. However, SV pharmacokinetic parameters were not significantly affected by silymarin pretreatment. Therefore, these changes indicated that drug-drug interactions may occur after co-administration of silymarin and SV.

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Pharmacokinetics of Florfenicol in Healthy Pigs and in Pigs Experimentally Infected with Actinobacillus pleuropneumoniae

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.47.2.820-823.2003 ◽

2003 ◽

Vol 47 (2) ◽

pp. 820-823 ◽

Cited By ~ 52

Author(s):

Jianzhong Liu ◽

Ki-Fai Fung ◽

Zhangliu Chen ◽

Zhenling Zeng ◽

Jie Zhang

Keyword(s):

Half Life ◽

Clinical Signs ◽

Actinobacillus Pleuropneumoniae ◽

Pharmacokinetic Parameters ◽

X Rays ◽

Time Data ◽

Time Curve ◽

Chromatography Method ◽

Concentration Time ◽

Significant Difference

ABSTRACT A comparative in vivo pharmacokinetic study of florfenicol was conducted in 18 crossbred pigs infected with Actinobacillus pleuropneumoniae following intravenous (i.v.), intramuscular (i.m.), or oral (p.o.) administration of a single dose of 20 mg/kg. The disease model was confirmed by clinical signs, X rays, pathohistologic examinations, and organism isolation. Florfenicol concentrations in plasma were determined by a validated high-performance liquid chromatography method with UV detection at a wavelength of 223 nm. Pharmacokinetic parameters were calculated by using the MCPKP software (Research Institute of Traditional Chinese Veterinary Medicine, Lanzhou, China). The disposition of florfenicol after a single i.v. bolus was described by a two-compartment model with values for the half-life at α phase (t 1/2α), the half-life at β phase (t 1/2β), the area under the concentration-time curve (AUC0-∞), and the volume of distribution at steady state (V ss) of 0.37 h, 2.91 h, 64.86 μg · h/ml, and 1.2 liter/kg, respectively. The concentration-time data fitted the one-compartment (after i.m.) and two-compartment (after p.o.) models with first-order absorption. The values for the maximum concentration of drug in serum (C max), t 1/2α, t 1/2β, and bioavailability after i.m. and p.o. dosing were 4.00 and 8.11 μg/ml, 0.12 and 3.91 h, 13.88 and 16.53 h, and 122.7 and 112.9%, respectively, for the two models. The study showed that florfenicol was absorbed quickly and completely, distributed widely, and eliminated slowly in the infected pigs, and there was no statistically significant difference between the pharmacokinetic profiles for the infected and healthy pigs.

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PHARMACOKINETIC COMPARISON OF MONTELUKAST SODIUM FORMULATIONS AFTER A SINGLE ORAL DOSE IN HEALTHY GUINEA PIGS

Asian Journal of Pharmaceutical and Clinical Research ◽

10.22159/ajpcr.2019.v12i2.29279 ◽

2019 ◽

pp. 165-169

Author(s):

NEELAM SINGH ◽

Giriraj T Kulkarni ◽

Yatendra Kumar ◽

GIRIRAJ T KULKARNI

Keyword(s):

Plasma Concentration ◽

Oral Dose ◽

Single Oral Dose ◽

Guinea Pigs ◽

Elimination Rate ◽

Pharmacokinetic Parameters ◽

Time Data ◽

Concentration Time ◽

Montelukast Sodium ◽

Significant Difference

Objective: Pharmacokinetic evaluation of montelukast sodium chronomodulated capsules (sustained-release solid dispersion of drug enclosed in pH-sensitive film-coated hard gelatin shell) and marketed tablets has been carried out in this study. Methods: A single oral dose of prepared capsules and marketed conventional tablets was administered in healthy male Dunkin-Hartley albino guinea pigs. Blood samples were collected at different time intervals and plasma concentration of drug was determined by reversed-phase high-performance liquid chromatography. Different pharmacokinetic parameters were assessed from plasma drug concentration-time profile by one-compartment model, first-order kinetics. Results: Pharmacokinetic parameters such as time to reach maximum concentration, elimination rate constant, elimination half-life, and mean residence time data indicates that drug release from chronomodulated capsules is significantly prolonged with initial release lag time of 3.5–4 h in comparison with marketed conventional tablets. However, maximum drug plasma concentration, area under the concentration-time curve, and apparent volume of distribution values show non-significant difference between capsules and marketed tablets. Conclusion: The findings specified that capsules were providing time controlled delivery of drug at a desired rate for prolonged time, which may be helpful for the prevention of episodic attack of asthma in early morning hours.

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Development of Paroxetine Hydrochloride Single Layer Controlled-Release Tablets Based on 32 Factorial Design

Pharmaceutics ◽

10.3390/pharmaceutics10040243 ◽

2018 ◽

Vol 10 (4) ◽

pp. 243 ◽

Cited By ~ 1

Author(s):

Yao Yang ◽

Zhengwei Huang ◽

Xuan Zhang ◽

Jinyuan Li ◽

Ying Huang ◽

...

Keyword(s):

Controlled Release ◽

Single Layer ◽

Suicide Mortality ◽

Pharmacokinetic Parameters ◽

Release Mechanism ◽

Time Curve ◽

Layer Separation ◽

Significant Difference ◽

Paroxetine Hydrochloride ◽

Controlled Release Tablets

Major depressive disorder (MDD) is one of the main contributors to disability and suicide mortality globally. Paroxetine hydrochloride (PHH) is the most potent antidepressant used for MDD treatment. Due to its reduced side effects PAXIL® CR is a widely-used controlled-release formulation of PHH. However, the complicated double-layer production of PAXIL® CR faces the risk of layer separation. In this study, PHH enteric coating single layer controlled-release tablets (PHH-EC-SLTs) were designed as a simplified substitution of PAXIL® CR through a rational formulation screening. The optimized PHH-EC-SLTs showed similar release behaviors in vitro to PAXIL® CR and the release profiles corresponded to a zero-order release model (R2 = 0.9958). Polymer matrix erosion was the main release mechanism, according to the fitting exponents n > 1 in the Korsmeyer-Pappas model. Crucial pharmacokinetic parameters including peak-reaching time (Tmax), peak concentration (Cmax) and the area under the blood level-time curve (AUC0-48) of PHH-EC-SLTs and PAXIL® CR had no significant difference (p > 0.05) and the relative bioavailability (F = 97.97%) of PHH-EC-SLTs demonstrated their similar pharmacokinetic profiles in vivo. In view of avoiding layer separation risk and simplifying the preparation processing, the self-made PHH-EC-SLTs could be considered as a safe and economic alternative to PAXIL® CR.

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Lack of Effect of Zafirlukast on the Pharmacokinetics of Azithromycin, Clarithromycin, and 14-Hydroxyclarithromycin in Healthy Volunteers

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.43.5.1152 ◽

1999 ◽

Vol 43 (5) ◽

pp. 1152-1155 ◽

Cited By ~ 16

Author(s):

Kevin W. Garey ◽

Charles A. Peloquin ◽

Paul G. Godo ◽

Anne N. Nafziger ◽

Guy W. Amsden

Keyword(s):

Steady State ◽

Healthy Subjects ◽

High Performance ◽

Pharmacokinetic Parameters ◽

Steady State Concentration ◽

Open Label ◽

Time Curve ◽

Data Analyses ◽

Concentration Time ◽

State Concentration

ABSTRACT This randomized, open-label, crossover study was conducted to investigate whether the coadministration of zafirlukast would affect the pharmacokinetics of azithromycin, clarithromycin, or 14-hydroxyclarithromycin (14-OHC). Twelve healthy subjects (six males and six females) received single 500-mg doses of azithromycin and clarithromycin with and without zafirlukast given to a steady-state concentration. Blood was collected prior to all macrolide doses and for 3 and 10 days after each clarithromycin and azithromycin dose, respectively. Serum was assayed for azithromycin, clarithromycin, and 14-OHC concentrations by validated high-performance liquid chromatography assay systems. Data analyses were done by noncompartmental and nonparametric methods. Analysis of the patients indicated that the addition of steady-state concentrations of zafirlukast did not significantly alter the pharmacokinetic parameters of or overall exposure (based on the area under the concentration-time curve) to azithromycin, clarithromycin, and 14-OHC. While zafirlukast is a known inhibitor of CYP3A4, it does not appear to exert a clinically or statistically significant pharmacokinetic effect on azithromycin, clarithromycin, or 14-OHC.

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Development of a Population Pharmacokinetic Model for Parecoxib and Its Active Metabolite Valdecoxib after Parenteral Parecoxib Administration in Children

Anesthesiology ◽

10.1097/aln.0b013e31825154ef ◽

2012 ◽

Vol 116 (5) ◽

pp. 1124-1133 ◽

Cited By ~ 11

Author(s):

Bruce Hullett ◽

Sam Salman ◽

Sean J. O'Halloran ◽

Deborah Peirce ◽

Kylie Davies ◽

...

Keyword(s):

Active Metabolite ◽

Pharmacokinetic Model ◽

Inhibitory Concentration ◽

Prediction Interval ◽

Cyclooxygenase 2 ◽

Pharmacokinetic Parameters ◽

Population Pharmacokinetic ◽

Time Curve ◽

Concentration Time

Background Parecoxib is a cyclooxygenase-2 selective inhibitor used in management of postoperative pain in adults. This study aimed to provide pediatric pharmacokinetic information for parecoxib and its active metabolite valdecoxib. Methods Thirty-eight children undergoing surgery received parecoxib (1 mg/kg IV to a maximum of 40 mg) at induction of anesthesia, and plasma samples were collected for drug measurement. Population pharmacokinetic parameters were estimated using nonlinear mixed effects modeling. Area under the valdecoxib concentration-time curve and time above cyclooxygenase-2 in vitro 50% inhibitory concentration for free valdecoxib were simulated. Results A three-compartment model best represented parecoxib disposition, whereas one compartment was adequate for valdecoxib. Age was linearly correlated with parecoxib clearance (5.0% increase/yr). There was a sigmoid relationship between age and both valdecoxib clearance and distribution volume. Time to 50% maturation was 87 weeks postmenstrual age for both. In simulations using allometric-based doses the 90% prediction interval of valdecoxib concentration-time curve in children 2-12.7 yr included the mean for adults given 40 mg parecoxib IV. Simulated free valdecoxib plasma concentration remained above the in vitro 50% inhibitory concentrations for more than 12 h. In children younger than 2 yr, a dose reduction is likely required due to ongoing metabolic maturation. Conclusions The final pharmacokinetic model gave a robust representation of parecoxib and valdecoxib disposition. Area under the valdecoxib concentration-time curve was similar to that in adults (40 mg), and simulated free valdecoxib concentration was above the cyclooxygenase-2 in vitro 50% inhibitory concentration for free valdecoxib for at least 12 h.

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Limited Sampling Strategies to Estimate the Area under the Concentration-time Curve

Methods of Information in Medicine ◽

10.3414/me11-01-0071 ◽

2012 ◽

Vol 51 (05) ◽

pp. 383-394 ◽

Cited By ~ 5

Author(s):

M. Fukumoto ◽

L. Bax ◽

A. Kohno ◽

Y. Morishita ◽

H. Tsuruta

Keyword(s):

Rate Constant ◽

Elimination Rate ◽

Estimation Method ◽

Pharmacokinetic Parameters ◽

Good Precision ◽

Sampling Strategies ◽

Time Curve ◽

New Methods ◽

Limited Sampling ◽

Concentration Time

SummaryBackground: Over 100 limited sampling strategies (LSSs) have been proposed to reduce the number of blood samples necessary to estimate the area under the concentration-time curve (AUC). The conditions under which these strategies succeed or fail remain to be clarified.Objectives: We investigated the accuracy of existing LSSs both theoretically and numerically by Monte Carlo simulation. We also proposed two new methods for more accurate AUC estimations.Methods: We evaluated the following existing methods theoretically: i) nonlinear curve fitting algorithm (NLF), ii) the trapezium rule with exponential curve approximation (TZE), and iii) multiple linear regression (MLR). Taking busulfan (BU) as a test drug, we generated a set of theoretical concentration-time curves based on the identified distribution of pharmacokinetic parameters of BU and re-evaluated the existing LSSs using these virtual validation profiles. Based on the evaluation results, we improved the TZE so that unrealistic parameter values were not used. We also proposed a new estimation method in which the most likely curve was selected from a set of pre-generated theoretical concentration-time curves.Results: Our evaluation, based on clinical profiles and a virtual validation set, revealed: i) NLF sometimes overestimated the absorption rate constant Ka, ii) TZE overestimated AUC over 280% when Ka is small, and iii) MLR underestimated AUC over 30% when the elimination rate constant Ke is small. These results were consistent with our mathematical evaluations for these methods. In contrast, our two new methods had little bias and good precision.Conclusions: Our investigation revealed that existing LSSs induce different but specific biases in the estimation of AUC. Our two new LSSs, a modified TZE and one using model concentration-time curves, provided accurate and precise estimations of AUC.

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Pharmacokinetics of ciclopirox prodrug, a novel agent for the treatment of bladder cancer, in animals and humans.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e14705 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e14705-e14705 ◽

Cited By ~ 2

Author(s):

Scott James Weir ◽

Robyn Wood ◽

Michael Jay Baltezor ◽

Greg Reed ◽

Amanda E Brinker ◽

...

Keyword(s):

Phase 1 ◽

Systemic Exposure ◽

Absolute Bioavailability ◽

Pharmacokinetic Parameters ◽

Time Data ◽

Elimination Half ◽

Urine Drug ◽

Ic50 Values

e14705 Background: Ciclopirox Prodrug (CPX-POM) is a novel anticancer agent currently being evaluated in patients with advanced solid tumors participating in a First-in-Human, Phase 1 safety, dose tolerance, pharmacokinetics (PK) and pharmacodynamics trial at four US sites. In vitro and in vivo preclinical proof of principle was established in high grade human urothelial cancer cell lines as well as a mouse model of bladder cancer.Methods: A series of in vivo PK studies were conducted in mice, rats and dogs to characterize the absolute bioavailability of CPX following intravenous (IV), subcutaneous (SC) and oral administration of CPX-POM. The single dose and steady-state plasma and urine pharmacokinetics of CPX-POM are also currently being characterized in patients participating in the ongoing Phase 1 trial. Plasma and urine concentrations of the prodrug and metabolites were determined by LC-MS/MS validated in each specie and matrix. Non-parametric pharmacokinetic parameters were generated from resultant plasma and urine drug and metabolite concentration-time data. Results: CPX-POM is rapidly and completely metabolized to CPX in blood via circulating phosphatases in animals and humans. CPX is completely bioavailable following IV CPX-POM administration in mice, rats and dogs. CPX and its major inactive glucuronide metabolite (CPX-G) are extensively eliminated in urine in all animal species. SC administration of CPX-POM demonstrated excellent bioavailability in rats and dogs. Following IV administration of 30-900 mg/m2CPX-POM to patients, the apparent elimination half-life of CPX ranged from 2 to 8 hours, CPX systemic exposure was dose-proportional and time-independent in cancer patients, and a major portion of the dose was eliminated as CPX-G. Conclusions: IV CPX-POM achieves plasma and urine CPX exposures that exceed in vitro IC50 values several-fold at well tolerated doses in animals and humans. CPX pharmacokinetics observed in animals were predictive of human systemic clearance based on allometric scaling. Clinical trial information: NCT03348514.

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Extended-Interval Gentamicin Dosing in Achieving Therapeutic Concentrations in Malaysian Neonates

The Journal of Pediatric Pharmacology and Therapeutics ◽

10.5863/1551-6776-20.2.119 ◽

2015 ◽

Vol 20 (2) ◽

pp. 119-127

Author(s):

Yee Shan Low ◽

Sin Li Tan ◽

Angeline SL Wan

Keyword(s):

Body Weight ◽

Gestational Age ◽

Trough Concentration ◽

Elimination Rate ◽

Dose Interval ◽

Pharmacokinetic Analysis ◽

Pharmacokinetic Parameters ◽

Creatinine Concentration ◽

Cross Sectional ◽

Significant Difference

OBJECTIVE: To evaluate the usefulness of extended-interval gentamicin dosing practiced in neonatal intensive care unit (NICU) and special care nursery (SCN) of a Malaysian hospital. METHODS: Cross-sectional observational study with pharmacokinetic analysis of all patients aged ≤28 days who received gentamicin treatment in NICU/SCN. Subjects received dosing according to a regimen modified from an Australian-based pediatric guideline. During a study period of 3 months, subjects were evaluated for gestational age, body weight, serum creatinine concentration, gentamicin dose/interval, serum peak and trough concentrations, and pharmacokinetic parameters. Descriptive percentages were used to determine the overall dosing accuracy, while analysis of variance (ANOVA) was conducted to compare the accuracy rates among different gestational ages. Pharmacokinetic profile among different gestational age and body weight groups were compared by using ANOVA. RESULTS: Of the 113 subjects included, 82.3% (n = 93) achieved therapeutic concentrations at the first drug-monitoring assessment. There was no significant difference found between the percentage of term neonates who achieved therapeutic concentrations and the premature group (87.1% vs. 74.4%), p = 0.085. A total of 112 subjects (99.1%) achieved desired therapeutic trough concentration of <2 mg/L. Mean gentamicin peak concentration was 8.52 mg/L (95% confidence interval [Cl], 8.13–8.90 mg/L) and trough concentration was 0.54 mg/L (95% CI, 0.48–0.60 mg/L). Mean volume of distribution, half-life, and elimination rate were 0.65 L/kg (95% CI, 0.62–0.68 L/kg), 6.96 hours (95% CI, 6.52–7.40 hours), and 0.11 hour−1 (95% CI, 0.10–0.11 hour−1), respectively. CONCLUSION: The larger percentage of subjects attaining therapeutic range with extended-interval gentamicin dosing suggests that this regimen is appropriate and can be safely used among Malaysian neonates.

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Inhibition and Induction by Poziotinib of Different Rat Cytochrome P450 Enzymes In Vivo and in an In Vitro Cocktail Method

Frontiers in Pharmacology ◽

10.3389/fphar.2020.593518 ◽

2021 ◽

Vol 11 ◽

Author(s):

Jinhui Wang ◽

Feifei Chen ◽

Hui Jiang ◽

Jia Xu ◽

Deru Meng ◽

...

Keyword(s):

Cytochrome P450 ◽

Rat Liver ◽

Clinical Investigation ◽

Liver Microsomes ◽

Pharmacokinetic Parameters ◽

Rat Liver Microsomes ◽

Cytochrome P450 Enzymes ◽

Significant Difference

Poziotinib is an orally active, irreversible, pan-HER tyrosine kinase inhibitor used to treat non-small cell lung cancer, breast cancer, and gastric cancer. Poziotinib is currently under clinical investigation, and understanding its drug-drug interactions is extremely important for its future development and clinical application. The cocktail method is most suitable for evaluating the activity of cytochrome P450 enzymes (CYPs). As poziotinib is partially metabolized by CYPs, cocktail probes are used to study the interaction between drugs metabolized by each CYP subtype. Midazolam, bupropion, dextromethorphan, tolbutamide, chlorzoxazone, phenacetin, and their metabolites were used to examine the effects of poziotinib on the activity of cyp1a2, 2b1, 2d1, 2c11, 2e1, and 3a1/2, respectively. The in vitro experiment was carried out by using rat liver microsomes (RLMs), whereas the in vivo experiment involved the comparison of the pharmacokinetic parameters of the probes after co-administration with poziotinib to rats to those of control rats treated with only probes. UPLC-MS/MS was used to detect the probes and their metabolites in rat plasma and rat liver microsomes. The in vitro results revealed that the half-maximal inhibitory concentration values of bupropion and tolbutamide in RLMs were 8.79 and 20.17 μM, respectively, indicating that poziotinib showed varying degrees of inhibition toward cyp2b1 and cyp2c11. Poziotinib was a competitive inhibitor of cyp2b1 and cyp2c11, with Ki values of 16.18 and 17.66 μM, respectively. No time- or concentration-dependence of inhibition by poziotinib was observed toward cyp2b1 and cyp2c11 in RLMs. Additionally, no obvious inhibitory effects were observed on the activity of cyp1a2, cyp2d1, cyp2e1, and cyp3a1/2. In vivo analysis revealed that bupropion, tolbutamide, phenacetin, and chlorzoxazone showed significantly different pharmacokinetic parameters after administration (p < 0.05); there was no significant difference in the pharmacokinetic parameters of dextromethorphan and midazolam. These results show that poziotinib inhibited cyp2b1 and cyp2c11, but induced cyp1a2 and cyp2e1 in rats. Thus, poziotinib inhibited cyp2b1 and cyp2c11 activity in rats, suggesting the possibility of interactions between poziotinib and these CYP substrates and the need for caution when combining them in clinical settings.

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