Study on the Effect of Three CYP2C9 Variants on Drug–Drug Interaction Related to Six Drugs In Vitro by LC–MS/MS Method

2022 ◽  
Author(s):  
Zhiping Sun ◽  
Lingli He ◽  
Qingqing Yang ◽  
Haizhi Zhang ◽  
Weiren Xu ◽  
...  
2020 ◽  
Vol 21 ◽  
Author(s):  
Xuan Yu ◽  
Zixuan Chu ◽  
Jian Li ◽  
Rongrong He ◽  
Yaya Wang ◽  
...  

Background: Many antibiotics have a high potential for having an interaction with drugs, as perpetrator and/or victim, in critically ill patients, and particularly in sepsis patients. Methods: The aim of this review is to summarize the pharmacokinetic drug-drug interaction (DDI) of 45 antibiotics commonly used in sepsis care in China. Literature mining was conducted to obtain human pharmacokinetics/dispositions of the antibiotics, their interactions with drug metabolizing enzymes or transporters, and their associated clinical drug interactions. Potential DDI is indicated by a DDI index > 0.1 for inhibition or a treated-cell/untreated-cell ratio of enzyme activity being > 2 for induction. Results: The literature-mined information on human pharmacokinetics of the identified antibiotics and their potential drug interactions is summarized. Conclusion: Antibiotic-perpetrated drug interactions, involving P450 enzyme inhibition, have been reported for four lipophilic antibacterials (ciprofloxacin, erythromycin, trimethoprim, and trimethoprim-sulfamethoxazole) and three lipophilic antifungals (fluconazole, itraconazole, and voriconazole). In addition, seven hydrophilic antibacterials (ceftriaxone, cefamandole, piperacillin, penicillin G, amikacin, metronidazole, and linezolid) inhibit drug transporters in vitro. Despite no reported clinical PK drug interactions with the transporters, caution is advised in the use of these antibacterials. Eight hydrophilic antibacterials (all β-lactams; meropenem, cefotaxime, cefazolin, piperacillin, ticarcillin, penicillin G, ampicillin, and flucloxacillin), are potential victims of drug interactions due to transporter inhibition. Rifampin is reported to perpetrate drug interactions by inducing CYP3A or inhibiting OATP1B; it is also reported to be a victim of drug interactions, due to the dual inhibition of CYP3A4 and OATP1B by indinavir. In addition, three antifungals (caspofungin, itraconazole, and voriconazole) are reported to be victims of drug interactions because of P450 enzyme induction. Reports for other antibiotics acting as victims in drug interactions are scarce.


2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Qun Zhang ◽  
Zengqiang Qu ◽  
Yanqing Zhou ◽  
Jin Zhou ◽  
Junwei Yang ◽  
...  

Abstract Background Cornin is a commonly used herb in cardiology for its cardioprotective effect. The effect of herbs on the activity of cytochrome P450 enzymes (CYP450s) can induce adverse drug-drug interaction even treatment failure. Therefore, it is necessary to investigate the effect of cornin on the activity of CYP450s, which can provide more guidance for the clinical application of cornin. Methods Cornin (100 μM) was incubated with eight isoforms of CYP450s, including CYP1A2, 2A6, 3A4, 2C8, 2C9, 2C19, 2D6, and 2E1, in pooled human liver microsomes. The inhibition model and corresponding parameters were also investigated. Results Cornin exerted significant inhibitory effect on the activity of CYP3A4, 2C9, and 2E1 in a dose-dependent manner with the IC50 values of 9.20, 22.91, and 14.28 μM, respectively (p < 0.05). Cornin inhibited the activity of CYP3A4 non-competitively with the Ki value of 4.69 μM, while the inhibition of CYP2C9 and 2E1 by cornin was competitive with the Ki value of 11.31 and 6.54 μM, respectively. Additionally, the inhibition of CYP3A4 by cornin was found to be time-dependent with the KI/Kinact value of 6.40/0.055 min− 1·μM− 1. Conclusions The inhibitory effect of cornin on the activity of CYP3A4, 2C9, and 2E1 indicated the potential drug-drug interaction between cornin and drugs metabolized by these CYP450s, which needs further investigation and validation.


Pharmacology ◽  
2015 ◽  
Vol 95 (3-4) ◽  
pp. 133-138 ◽  
Author(s):  
Sai-Zhen Chen ◽  
Pei-Pei Pan ◽  
Shuang-Hu Wang ◽  
Jun Luo ◽  
Guo-Xin Hu ◽  
...  

2013 ◽  
Vol 57 (10) ◽  
pp. 4982-4989 ◽  
Author(s):  
Kirsten M. Stray ◽  
Rujuta A. Bam ◽  
Gabriel Birkus ◽  
Jia Hao ◽  
Eve-Irene Lepist ◽  
...  

ABSTRACTA once-daily single-tablet antiretroviral regimen containing tenofovir (TFV) disoproxil fumarate, emtricitabine (FTC), elvitegravir (EVG), and cobicistat (COBI) is an approved combination for the treatment of patients infected with HIV. COBI and TFV have been reported to interact with distinct transporters in renal proximal tubules; while TFV is renally eliminated by a combination of glomerular filtration and tubular secretion via anion transporters OAT1, OAT3, and MRP4, COBI inhibits renal cation transporters, particularly MATE1, resulting in a measurable decrease in the tubular secretion of creatinine. To investigate the potential for a renal drug-drug interaction between TFV and COBIin vitro, the uptake of TFV in the presence and absence of COBI was determined in fresh human renal cortex tissue and in cells expressing the relevant renal transporters. At concentrations exceeding clinical protein-unbound plasma levels, COBI did not significantly inhibit the transport of TFV by the anion transporters OAT1, OAT3, and MRP4 (50% inhibitory concentrations [IC50s] of >15, 6.6, and 8.5 μM, respectively). Conversely, TFV had little or no effect on the cation transporters OCT2 and MATE1 (IC50> 100 μM). Consistent with studies using individual transporters, no increase in the accumulation of TFV in freshly isolated human renal cortex tissue or renal proximal tubule cells (RPTECs) was observed in the presence of COBI. Finally, COBI alone or in combination with FTC and EVG did not affect the sensitivity to TFV of cultured primary RPTECs or cells coexpressing OAT1 and MRP4. These results illustrate that COBI and TFV interact primarily with distinct renal transporters and indicate a low potential for pharmacokinetic renal drug-drug interaction.


Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 22-23
Author(s):  
Marianne Kjalke ◽  
Søren Andersen

Introduction: Lack of factor VIII/IX (FVIII/FIX) in hemophilia A/B (HA/HB), respectively, results in reduced thrombin generation, leading to recurrent/spontaneous bleeds. Concizumab is an anti-tissue factor pathway inhibitor (TFPI) monoclonal antibody, currently under clinical investigation for subcutaneous prophylaxis of HA/HB patients with/without inhibitors. Breakthrough bleeds occurring in HA/HB patients while on concizumab prophylaxis may be treated with FVIII/FIX. We aimed to compare the in vitro effect of recombinant FVIII (rFVIII) and FIX (rFIX) in HA and HB plasma, respectively, in the absence or presence of concizumab. Methods: rFVIII/rFIX was added to HA/HB pooled plasma at 0.25, 0.5 or 1 IU/mL (corresponding to post-administration plasma concentrations of 12.5, 25 and 50 IU/kg rFVIII and 12.5−25, 25−50 and 50−100 IU/kg rFIX) in the absence or presence of concizumab (1,500, 4,500 or 15,000 ng/mL). In a separate experiment, 33 plasma samples from eight HA patients, who were on concizumab prophylaxis as part of the phase 2 explorer5 trial (NCT03196297), were spiked with 0.5, 1 and 1.5 IU/mL rFVIII. Pre-dose samples (before concizumab prophylaxis) from seven of these patients were also included. Thrombin generation was measured after initiation with 1 pM tissue factor (PPP-Low, Thrombinoscope). Statistical analysis of the effects conferred by each (combination of) drug(s) was performed by ANOVA analyses. Results: A significant (p&lt;0.001) and concentration-dependent increase in thrombin peak was observed when HA plasma pool samples were spiked with rFVIII, both in the absence and presence of concizumab. Likewise, concizumab increased the thrombin peak both in the absence and in presence of rFVIII. Increasing concizumab from 1,500 to 4,500 and 15,000 ng/mL only slightly increased the thrombin peak further, demonstrating that a close-to-maximal effect on thrombin peak was achieved at 1,500 ng/mL concizumab. The effects of concizumab and rFVIII were mainly additive with an up to 20% additional effect caused by drug-drug interaction. The addition of rFVIII to explorer5 patient plasma samples resulted in a significant and concentration-dependent increase in thrombin peak. The effects observed for rFVIII and concizumab were exclusively additive. The thrombin peak obtained with 1.0 IU/mL rFVIII before concizumab administration was lower than with 0.5 IU/mL rFVIII in the presence of concizumab. This suggests that a 2-fold reduced rFVIII dose may be sufficient to achieve the same plasma thrombin generation capacity as with the standard rFVIII dose in the absence of concizumab. The addition of rFIX to a HB plasma pool increased the thrombin peak significantly (p&lt;0.001) and in a concentration-dependent manner both in the absence and presence of concizumab (1,500 ng/mL). Likewise, concizumab increased the thrombin peak at all rFIX concentrations (p&lt;0.001). Increasing concizumab from 1,500 to 4,500 and 15,000 ng/mL had no or limited further effect. The effects of concizumab and rFIX were mainly additive with an up to 10% effect conferred by negative drug-drug interaction for 1 IU/mL rFIX combined with concizumab &gt;1,500 ng/mL and 0.5 IU/mL rFIX combined with 15,000 ng/mL concizumab, i.e., a 10% smaller effect of rFIX was observed in the presence of concizumab than in its absence. The thrombin peak obtained upon adding 1.0 IU/mL rFIX to plasma without concizumab was similar to the thrombin peak in the presence of concizumab and 0.5 IU/mL rFIX. This suggests that in the presence of concizumab, a 2-fold reduced dose of rFIX would be sufficient to obtain the same plasma thrombin generation capacity as with 1.0 IU/mL rFIX in the absence of concizumab. Conclusion: rFVIII/rFIX increased the thrombin peak in HA and HB plasma, respectively, both in the absence and presence of concizumab. The combined effects of rFVIII/rFIX with concizumab were mainly additive with an up to 20% additional effect caused by drug-drug interaction with rFVIII and a 10% reduction with rFIX. No signs of exaggerated thrombin generation were observed by combining concizumab with rFVIII/rFIX. Therefore, the data support rFVIII/rFIX use for bleed treatment in patients on concizumab prophylaxis. As rFVIII/rFIX and concizumab have additive effects in terms of thrombin generation capacity, data suggest that clinical effectiveness could be achieved with rFVIII/rFIX doses in the lower range recommended for such products. Disclosures Kjalke: Novo Nordisk A/S: Current Employment, Current equity holder in publicly-traded company. Andersen:Novo Nordisk A/S: Current Employment, Current equity holder in publicly-traded company.


2020 ◽  
Vol 45 (4) ◽  
pp. 433-444
Author(s):  
Roland Heinig ◽  
Michael Gerisch ◽  
Michaela Bairlein ◽  
Johannes Nagelschmitz ◽  
Stephanie Loewen

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