Pharmacokinetics of flucloxacillin and its metabolites in patients with renal failure: Impact on liver toxicity

Abstract

Based on data from perfused rat livers, high biliary concentrations of 5-OH-FX might also be observed in our patients explaining why LDH, bilirubin, and alkaline phosphatase were elevated in up to 8/12 patients after repeated infusion of flucloxacillin. Liver toxicity of flucloxacillin might therefore be observed in patients with renal impairment after continuously elevated 5-OH-FX levels. .

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

“…The mass increase of 18 relative to flucloxacillin (m/z 454.059) indicates that this product most likely corresponds to the penicilloic acid formed by hydrolysis of the β‐lactam ring of flucloxacillin which is not dependent on CYP‐activity. The penicilloic acid of 5′‐HM‐FLX, which was identified in urine (Maier‐Salamon et al ., ), was not detectable under the incubation conditions used. After checking the linearity of product formation with time, the enzyme kinetics of 5′‐HM‐FLX formation by pooled HLM was studied in 10 min incubations by varying the concentration of flucloxacillin from 10 to 500 μM.…”

“…demonstrated that in the 713 human livers analysed, CYP3A4 levels varied markedly, ranging from 0 to 601 pmol·mg −1 protein (Achour et al ., ). This large variability can contribute to the interindividual variability in plasma concentrations of 5′‐HM‐FLX (Maier‐Salamon et al ., ). As mentioned, next to CYP3A4, another CYP, CYP3A7, showed high activity in flucloxacillin hydroxylation.…”

“…Many studies have investigated the pharmacokinetics of flucloxacillin in groups of healthy volunteers or patients (Thijssen and Wolters, 1982;Adam et al, 1983;Gath et al, 1995;Røder et al, 1995;Landersdorfer et al, 2007;Dijkmans et al, 2012;Maier-Salamon et al, 2017). Dependent on the dose regimen and route of administration (by i.v.…”

“…infusion and/or orally), the maximal plasma concentration (C max ) of flucloxacillin can range 50 to 790 μM. Systemic clearance of flucloxacillin appears to be mainly by renal clearance (65-71%) (Landersdorfer et al, 2007;Maier-Salamon et al, 2017). Non-renal clearance of flucloxacillin occurs predominantly by cytochrome P450-mediated hydroxylation of flucloxacillin to 5 0 -HM-FLX and partly by hydrolysis to the corresponding penicilloic acid (Figure 1).…”

<i><b>In silico</b></i><b> analysis of interactions of flucloxacillin and its metabolites with </b><i><b>HLA-B*57:01</b></i><i><b> </b></i>

“…Maier-Salamon et al [10] have reported that the biliary concentration of 5-OH-FX is high and the liver toxicity of FX might be due to the continuously elevated 5-OH-FX. The present docking simulations have shown that the binding affinity of 5-OH-FX to HLA-B*57:01 is significantly high.…”