Growth and development affect drug‐metabolizing enzyme activity thus could alter the metabolic profile of a drug. Traditional studies to create metabolite profiles and study the routes of excretion are unethical in children due to the high radioactive burden. To overcome this challenge, we aimed to show the feasibility of an absorption, distribution, metabolism, and excretion (ADME) study using a [14C]midazolam microtracer as proof of concept in children. Twelve stable, critically ill children received an oral [14C]midazolam microtracer (20 ng/kg; 60 Bq/kg) while receiving intravenous therapeutic midazolam. Blood was sampled up to 24 hours after dosing. A time‐averaged plasma pool per patient was prepared reflecting the mean area under the curve plasma level, and subsequently one pool for each age group (0–1 month, 1–6 months, 0.5–2 years, and 2–6 years). For each pool [14C]levels were quantified by accelerator mass spectrometry, and metabolites identified by high resolution mass spectrometry. Urine and feces (n = 4) were collected up to 72 hours. The approach resulted in sufficient sensitivity to quantify individual metabolites in chromatograms. [14C]1‐OH‐midazolam‐glucuronide was most abundant in all but one age group, followed by unchanged [14C]midazolam and [14C]1‐OH‐midazolam. The small proportion of unspecified metabolites most probably includes [14C]midazolam‐glucuronide and [14C]4‐OH‐midazolam. Excretion was mainly in urine; the total recovery in urine and feces was 77–94%. This first pediatric pilot study makes clear that using a [14C]midazolam microtracer is feasible and safe to generate metabolite profiles and study recovery in children. This approach is promising for first‐in‐child studies to delineate age‐related variation in drug metabolite profiles.
Background and Purpose: Realistic models predicting hepatobiliary processes in health and disease are lacking. We therefore aimed to develop a physiologically relevant human liver model consisting of normothermic machine perfusion (NMP) of explanted diseased human livers that can be used to investigate hepatic first-pass, clearance, biliary excretion and drug-drug interactions. Experimental approach: Eleven livers were included in the study, seven with a cirrhotic and four with a non-cirrhotic disease background. After explantation of the diseased liver, the liver artery and portal vein were reconstructed followed by NMP. After 120 minutes of perfusion, a drug cocktail (rosuvastatin, digoxin, metformin and furosemide) was administered to the portal vein and 120 minutes later, a second bolus of the drug cocktail was co-administered with drug inhibitors to study relevant drug-drug interactions. Key results: The explanted livers showed good viability and functionality after explantation and 360 minutes of NMP. Hepatic first-pass and clearance of rosuvastatin and digoxin showed to be the most affected by cirrhosis with an increase in Cmax of 10.03 and 2.89 times, respectively, compared to non-cirrhotic livers. No major differences were observed for metformin and furosemide. Drug-drug interaction of rosuvastatin or digoxin with inhibitors were more pronounced in non-cirrhotic livers compared to cirrhotic livers. Conclusions and Implications: Our results demonstrated that explanted cirrhotic and non-cirrhotic livers were suitable for NMP and we demonstrated the applicability to study hepatic first pass, clearance, biliary excretion and drug-drug interaction. This model can be applied in a variety of research settings for hepatology, transplantation and pharmacology
Realistic models predicting hepatobiliary processes in health and disease are lacking. We therefore aimed to develop a physiologically relevant human liver model consisting of normothermic machine perfusion (NMP) of explanted diseased human livers that can assess hepatic extraction, clearance, biliary excretion, and drug-drug interaction (DDI). Eleven livers were included in the study, seven with a cirrhotic and four with a noncirrhotic disease background. After explantation of the diseased liver, NMP was initiated. After 120 minutes of perfusion, a drug cocktail (rosuvastatin, digoxin, metformin, and furosemide; OATP1B1/1B3, P-gp, BCRP, and OCT1 model compounds) was administered to the portal vein and 120 minutes later, a second bolus of the drug cocktail was co-administered with perpetrator drugs to study relevant DDIs. The explanted livers showed good viability and functionality during 360 minutes of NMP. Hepatic extraction ratios close to in vivo reported values were measured. Hepatic clearance of rosuvastatin and digoxin showed to be the most affected by cirrhosis with an increase in maximum plasma concentration (C max ) of 11.50 and 2.89 times, respectively, compared with noncirrhotic livers. No major differences were observed for metformin and furosemide. Interaction of rosuvastatin or digoxin with perpetrator drugs were more pronounced in noncirrhotic livers compared with cirrhotic livers. Our results demonstrated that NMP of human diseased explanted livers is an excellent model to assess hepatic extraction, clearance, biliary excretion, and DDI. Gaining insight into pharmacokinetic profiles of OATP1B1/1B3, P-gp, BCRP, and OCT1 model compounds is a first step toward studying transporter functions in diseased livers.Accurate prediction of drug disposition in patients with and without hepatic diseases remains difficult, as appropriate models are lacking. The liver plays an important role in drug handling and impairment or alteration of its function may greatly affect multiple processes. Upon first liver pass, after oral administration, drug bioavailability as well as drug clearance may be altered thereby
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