Study Protocol for a Pilot, Open-Label, Prospective, and Observational Study to Evaluate the Pharmacokinetics of Drugs Administered to Patients during Extracorporeal Circulation; Potential of In Vivo Cytochrome P450 Phenotyping to Optimise Pharmacotherapy.

Santosh Kumar Sreevatsav Adiraju,Ivan Rapchuk,Kiran Shekar,Sussan Ghassabian,Maree T Smith,Peter Tesar,Rishendran Naidoo,John F Fraser,Stephen Belz

doi:10.3390/mps2020038

Santosh Kumar Sreevatsav Adiraju, Ivan Rapchuk + Show 7 more

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https://doi.org/10.3390/mps2020038

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Pharmacokinetic alterations of medications administered during surgeries involving cardiopulmonary bypass (CPB) and extracorporeal membrane oxygenation (ECMO) have been reported. The impact of CPB on the cytochrome P450 (CYP) enzymes’ activity is the key factor. The metabolic rates of caffeine, dextromethorphan, midazolam, omeprazole, and Losartan to the CYP-specific metabolites are validated measures of in vivo CYP 1A2, 2D6, 3A4, 2C19, and 2C9 activities, respectively. The study aim is to assess the activities of major CYPs in patients on extracorporeal circulation (EC). This is a pilot, prospective, open-label, observational study in patients undergoing surgery using EC and patients undergoing laparoscopic cholecystectomy as a control group. CYP activities will be measured on the day, and 1–2 days pre-surgery/3–4 days post-surgery (cardiac surgery and Laparoscopic cholecystectomy) and 1–2 days after starting ECMO, 1–2 weeks after starting ECMO, and 1–2 days after discontinuation from ECMO. Aforementioned CYP substrates will be administered to the patient and blood samples will be collected at 0, 1, 2, 4, and 6 h post-dose. Major CYP enzymes’ activities will be compared in each participant on the day, and before/after surgery. The CYP activities will be compared in three study groups to investigate the impact of CYPs on EC.

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More than 1 million cardiac operations using cardiopulmonary bypass (CPB) are performed annually worldwide [1]
Khabar et al [3] discussed the link between the contribution of potential pathological post-CPB phenomena, including endotoxin and the pro-inflammatory cytokines, TNF-α, IL-6, and IL-8 as their plasma concentrations were increased significantly compared with their pre-CPB levels [3]
There are several examples in the clinical literature whereby cytokines have been implicated in altering cytochrome P450 (CYP) isoenzyme activities during cardiopulmonary bypass [11] resulting in impaired metabolism of clinically important drugs leading to their accumulation in the body and potential the potential for causing adverse effects

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Introduction

More than 1 million cardiac operations using CPB are performed annually worldwide [1]. While CPB usually lasts a few hours, extracorporeal membrane oxygenation (ECMO), a modified application of CPB concept, provides longer-term extracorporeal life support (days to weeks) as a bridge to recovery or a bridge to transplant or a destination device [1]. Both CPB and ECMO necessitate exteriorisation of significant blood volumes to achieve extracorporeal oxygenation. The plasma concentrations of the major anti-inflammatory cytokine, IL-10, were significantly higher in the broncho alveolar lavage fluid of VV-treated animals [10]. There are several examples in the clinical literature whereby cytokines have been implicated in altering cytochrome P450 (CYP) isoenzyme activities during cardiopulmonary bypass [11] resulting in impaired metabolism of clinically important drugs leading to their accumulation in the body and potential the potential for causing adverse effects

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