Oral Drug Absorption and Drug Disposition in Critically Ill Cardiac Patients

Abstract

(1) Background: In critically ill cardiac patients, parenteral and enteral food and drug administration routes may be used. However, it is not well known how drug absorption and metabolism are altered in this group of adult patients. Here, we analyze drug absorption and metabolism in patients after cardiogenic shock using the pharmacokinetics of therapeutically indicated esomeprazole. (2) Methods: The pharmacokinetics of esomeprazole were analyzed in a consecutive series of patients with cardiogenic shock and controls before and after elective cardiac surgery. Esomeprazole was administered orally or with a nasogastric tube and once as an intravenous infusion. (3) Results: The maximum plasma concentration and AUC of esomeprazole were, on average, only half in critically ill patients compared with controls (p < 0.005) and remained lower even seven days later. Interestingly, esomeprazole absorption was also markedly compromised on day 1 after elective surgery. The metabolites of esomeprazole showed a high variability between patients. The esomeprazole sulfone/esomeprazole ratio reflecting CYP3A4 activity was significantly lower in critically ill patients even up to day 7, and this ratio was negatively correlated with CRP values (p = 0.002). The 5'-OH-esomeprazole and 5-O-desmethyl-esomeprazol ratios reflecting CYP2C19 activity did not differ significantly between critically ill and control patients. (4) Conclusions: Gastrointestinal drug absorption can be significantly reduced in critically ill cardiac patients compared with elective patients with stable cardiovascular disease. The decrease in bioavailability indicates that, under these conditions, any vital medication should be administered intravenously to maintain high levels of medications. After shock, hepatic metabolism via the CYP3A4 enzyme may be reduced.

Keywords: cardiogenic shock; enteral medication; esomeprazole; intensive care medication.

Figure 1

Intraindividual course of esomeprazole pharmacokinetic parameters: left ICU cohort (shades of blue); right elective surgery cohort (shades of green); shades represent individual patients.

Figure 2

Differences in Cmax between cohorts on the different days studied; outliers are marked by open circles and extreme outliers by asterisks.

Figure 3

Intra- and interindividual changes in CYP2C19 and CYP3A4 activity in ICU patients after shock (shades of blue) compared to patients undergoing elective cardiac surgery (shades of green); shades represent individual patients. Although there is significant scatter mainly caused by very low concentrations of the parent drug, the quite small ratios of esomeprazole sulfone/esomeprazole on days 1 and 3 are apparent in about 50% of patients after shock, and it is also apparent that these ratios recovered primarily on day 7. Low metabolic ratios after intravenous dosing are explained by the lack of first-pass metabolism. Furthermore, biotransformation in the elective surgery group was not compromised the day after cardiac surgery, although intestinal absorption and bioavailability were significantly compromised in these patients on that day.

Figure 4

Correlation between esomeprazole–sulfone/esomeprazole ratio and C-reactive protein. Data from both cohorts are combined in this analysis.

Figure 5

High serum lactate as an indicator of poor enteral drug absorption, as indicated by esomeprazole pharmacokinetics.