Assessment of the mass balance recovery and metabolite profile of avibactam in humans and in vitro drug-drug interaction potential.

Avibactam, a novel non-β-lactam β-lactamase inhibitor with activity against Ambler class A, class C, and some class D enzymes is being evaluated in combination with various β-lactam antibiotics to treat serious bacterial infections. The in vivo mass balance recovery and metabolite profile of [(14)C] avibactam (500 mg/1-h infusion) was assessed in six healthy male subjects, and a series of in vitro experiments evaluated the metabolism and drug-drug interaction potential of avibactam. In the mass balance study, measurement of plasma avibactam (using a validated liquid chromatography-tandem mass spectrometry method) and total radioactivity in plasma, whole blood, urine, and feces (using liquid scintillation counting) indicated that most of the avibactam was excreted unchanged in urine within 12 hours, with recovery complete (>97% of the administered dose) within 96 hours.

Disposition and metabolism of the specific endothelin A receptor antagonist zibotentan (ZD4054) in healthy volunteers.

Zibotentan (ZD4054) is a specific endothelin A (ET(A)) receptor antagonist that is in clinical development for the treatment of castration-resistant prostate cancer (CRPC) and has shown a promising signal for improvement in overall survival compared with placebo in a Phase II study of patients with metastatic CRPC. In this study, the pharmacokinetics, disposition and metabolism of zibotentan were evaluated following administration of a single oral dose of [(14)C]-zibotentan 15 mg to six healthy subjects. Zibotentan was rapidly absorbed, with the maximum zibotentan plasma concentration being observed 1 hour after administration.

The disposition and metabolism of zibotentan (ZD4054): an oral-specific endothelin A receptor antagonist in mice, rats and dogs.

Zibotentan (ZD4054) is an oral-specific endothelin A receptor antagonist in development for the treatment of castration-resistant prostate cancer. In a number of preclinical studies, the disposition and metabolism of zibotentan were investigated in mice, rats and dogs. Following oral and intravenous administration, zibotentan was slowly absorbed (maximal concentration at approximately 4 h) and rapidly excreted, with the majority being eliminated by 48 h.

The metabolism of [14C]-zibotentan (ZD4054) in rat, dog and human, the loss of the radiolabel and the identification of an anomalous peak, derived from the animal feed.

This paper presents an overview of a cross-species investigation of the metabolic fate of [(14)C]-zibotentan (ZD4054), with particular focus on the main analytical challenges encountered during the study. A combination of detection methods were used including HPLC coupled to UV, RAD and/or MS(MS), and (1)H NMR spectroscopy. The objective was to characterise and identify the major metabolites found in the circulation and excreta of rat and dog for comparison with those produced in human.

Evaluation of the use of UPLC-TOFMS with simultaneous [14C]-radioflow detection for drug metabolite profiling: application to propranolol metabolites in rat urine.

The non-selective beta-adrenergic receptor antagonist propranolol [1-(isopropylamino)-3-(1-naphthoxy)-2-propanol] is metabolised extensively in vivo. Enumerating and identifying the many metabolites that result from multiple biotransformations provides a considerable analytical challenge, greatly aided by efficient chromatography coupled to sensitive mass spectrometric detection. Here the use of the newly introduced high-resolution technique of "ultra performance liquid chromatography" (UPLC) linked to quadrupole time-of-flight mass spectrometry (TOFMS) with simultaneous [(14)C]-radioflow detection was applied to rapid metabolite profiling.