Characterization of kinetics of human cytochrome <scp>P</scp>450s involved in bioactivation of flucloxacillin: inhibition of <scp>CYP</scp>3<scp>A</scp>‐catalysed hydroxylation by sulfaphenazole

Dekker, Stefan J.; Dohmen, Floor; Vermeulen, Nico; Commandeur, Jan N. M.

doi:10.1111/bph.14548

Cited by 14 publications

(8 citation statements)

References 49 publications

(77 reference statements)

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“…To quantify the contribution of the different CYP enzymes in VRC N -oxidation, two different experimental approaches were applied. In the first approach, the specific CYP inhibitors, loratadine (10 µM, CYP2C19), sulfaphenazole (10 µM, CYP2C9) and ketoconazole (0.1 µM, CYP3A4), as well as a mixture of the three, were added to VRC (0.5, 1, 2, 3 µM) incubations in HLM ( n = 3, t reac .= 15 and 25 min) [ 52 , 53 , 54 , 55 , 56 , 57 , 58 ]. The reaction velocities at the respective substrate concentrations in the presence and absence of the inhibitor were used to assess the contribution to NO formation.…”

Section: Methodsmentioning

confidence: 99%

Towards the Elucidation of the Pharmacokinetics of Voriconazole: A Quantitative Characterization of Its Metabolism

et al. 2022

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The small-molecule drug voriconazole (VRC) shows a complex and not yet fully understood metabolism. Consequently, its in vivo pharmacokinetics are challenging to predict, leading to therapy failures or adverse events. Thus, a quantitative in vitro characterization of the metabolism and inhibition properties of VRC for human CYP enzymes was aimed for. The Michaelis–Menten kinetics of voriconazole N-oxide (NO) formation, the major circulating metabolite, by CYP2C19, CYP2C9 and CYP3A4, was determined in incubations of human recombinant CYP enzymes and liver and intestine microsomes. The contribution of the individual enzymes to NO formation was 63.1% CYP2C19, 13.4% CYP2C9 and 29.5% CYP3A4 as determined by specific CYP inhibition in microsomes and intersystem extrapolation factors. The type of inhibition and inhibitory potential of VRC, NO and hydroxyvoriconazole (OH–VRC), emerging to be formed independently of CYP enzymes, were evaluated by their effects on CYP marker reactions. Time-independent inhibition by VRC, NO and OH–VRC was observed on all three enzymes with NO being the weakest and VRC and OH–VRC being comparably strong inhibitors of CYP2C9 and CYP3A4. CYP2C19 was significantly inhibited by VRC only. Overall, the quantitative in vitro evaluations of the metabolism contributed to the elucidation of the pharmacokinetics of VRC and provided a basis for physiologically-based pharmacokinetic modeling and thus VRC treatment optimization.

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Section: Methodsmentioning

confidence: 99%

Towards the Elucidation of the Pharmacokinetics of Voriconazole: A Quantitative Characterization of Its Metabolism

et al. 2022

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“…of the isoxazolyl-penicillin type is used to treat Gram-positive bacterial infections. Although CYP3A4 is involved in the metabolism of flucloxacillin, the drug itself does not show inhibition of CYP P450 isoenzymes, as shown by in vitro assays [6][7][8]. However, several cases have been reported in which flucloxacillin appeared to decrease levels of drugs metabolized by CYP3A4, such as voriconazole, cyclosporin A, and quinidine [8][9][10][11].…”

Section: Electronic Supplementary Materialsmentioning

confidence: 99%

Flucloxacillin decreases tacrolimus blood trough levels: a single-center retrospective cohort study

Veenhof

Schouw

Besouw

et al. 2020

Eur J Clin Pharmacol

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Purpose Tacrolimus and everolimus are widely used to prevent allograft rejection. Both are metabolized by the hepatic cytochrome P450 (CYP) enzyme CYP3A4 and are substrate for P-glycoprotein (P-gp). Drugs influencing the activity or expression of CYP enzymes and P-gp can cause clinically relevant changes in the metabolism of immunosuppressants. Several case reports have reported that flucloxacillin appeared to decrease levels of drugs metabolized by CYP3A4 and P-gp. The magnitude of this decrease has not been reported yet. Methods In this single-center retrospective cohort study, we compared the tacrolimus and everolimus blood trough levels (corrected for the dose) before, during, and after flucloxacillin treatment in eleven transplant patients (tacrolimus n = 11 patients, everolimus n = 1 patient, flucloxacillin n = 11 patients). Results The median tacrolimus blood trough level decreased by 37.5% (interquartile range, IQR 26.4-49.7%) during flucloxacillin treatment. After discontinuation of flucloxacillin, the tacrolimus blood trough levels increased by a median of 33.7% (IQR 22.5-51.4%). A Wilcoxon signed-rank test showed statistically significantly lower tacrolimus trough levels during treatment with flucloxacillin compared with before (p = 0.009) and after flucloxacillin treatment (p = 0.010). In the only available case with concomitant everolimus and flucloxacillin treatment, the same pattern was observed. Conclusions Flucloxacillin decreases tacrolimus trough levels, possibly through a CYP3A4 and/or P-gp-inducing effect. It is strongly recommended to closely monitor tacrolimus and everolimus trough levels during flucloxacillin treatment and up to 2 weeks after discontinuation of flucloxacillin.

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“…The pathogenesis of idiosyncratic DILI has often been related to CYP dependent drug metabolism, although the respective DILI was not assessed regarding causality for the drug under consideration study, nor was there any verification that the drug was really metabolized by CYP, and the CYP isoform involved in the metabolism of the drug commonly remained unconsidered. Based on published data [ 64 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 ], a recent analysis on drugs most implicated in idiosyncratic DILI assessed by RUCAM showed that only a portion of the drugs were substrates of hepatic microsomal CYP ( Table 3 ) [ 54 ].…”

Section: Overview On Molecular Toxicology In Human Idiosyncratic Dilimentioning

confidence: 99%

“…An assumed HLA association of liver injury by Amoxicillin-clavulanate has been proposed already in 1999, but results remained vague because cases were not assessed using RUCAM. Of clinical significance, Amoxicillin clavulanate was at rank #1 and Flucloxacillin at rank #2 among the drugs most implicated in RUCAM based DILI worldwide ( Table 3 ), and regarding mechanistic steps, drug metabolism via CYP is not essential for HLA mediated DILI because Amoxicillin clavulanate is not metabolized by CYP ( Table 3 ) [ 72 ] as opposed to Flucloxacillin that is metabolized ( Table 3 ) [ 73 ].…”

Section: Hepatic Immune Systemmentioning

confidence: 99%

Molecular Idiosyncratic Toxicology of Drugs in the Human Liver Compared with Animals: Basic Considerations

Teschke

2023

IJMS

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Drug induced liver injury (DILI) occurs in patients exposed to drugs at recommended doses that leads to idiosyncratic DILI and provides an excellent human model with well described clinical features, liver injury pattern, and diagnostic criteria, based on patients assessed for causality using RUCAM (Roussel Uclaf Causality Assessment Method) as original method of 1993 or its update of 2016. Overall, 81,856 RUCAM based DILI cases have been published until mid of 2020, allowing now for an analysis of mechanistic issues of the disease. From selected DILI cases with verified diagnosis by using RUCAM, direct evidence was provided for the involvement of the innate and adapted immune system as well as genetic HLA (Human Leucocyte Antigen) genotypes. Direct evidence for a role of hepatic immune systems was substantiated by (1) the detection of anti-CYP (Cytochrome P450) isoforms in the plasma of affected patients, in line with the observation that 65% of the drugs most implicated in DILI are metabolized by a range of CYP isoforms, (2) the DIAIH (drug induced autoimmune hepatitis), a subgroup of idiosyncratic DILI, which is characterized by high RUCAM causality gradings and the detection of plasma antibodies such as positive serum anti-nuclear antibodies (ANA) and anti-smooth muscle antibodies (ASMA), rarely also anti-mitochondrial antibodies (AMA), (3) the effective treatment with glucocorticoids in part of an unselected RUCAM based DILI group, and (4) its rare association with the immune-triggered Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) caused by a small group of drugs. Direct evidence of a genetic basis of idiosyncratic DILI was shown by the association of several HLA genotypes for DILI caused by selected drugs. Finally, animal models of idiosyncratic DILI mimicking human immune and genetic features are not available and further search likely will be unsuccessful. In essence and based on cases of DILI with verified diagnosis using RUCAM for causality evaluation, there is now substantial direct evidence that immune mechanisms and genetics can account for idiosyncratic DILI by many but not all implicated drugs, which may help understand the mechanistic background of the disease and contribute to new approaches of therapy and prevention.

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Characterization of kinetics of human cytochrome P450s involved in bioactivation of flucloxacillin: inhibition of CYP3A‐catalysed hydroxylation by sulfaphenazole

Cited by 14 publications

References 49 publications

Towards the Elucidation of the Pharmacokinetics of Voriconazole: A Quantitative Characterization of Its Metabolism

Towards the Elucidation of the Pharmacokinetics of Voriconazole: A Quantitative Characterization of Its Metabolism

Flucloxacillin decreases tacrolimus blood trough levels: a single-center retrospective cohort study

Molecular Idiosyncratic Toxicology of Drugs in the Human Liver Compared with Animals: Basic Considerations

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