Intestinal Drug Absorption After Subarachnoid Hemorrhage and Elective Neurosurgery: Insights From Esomeprazole Pharmacokinetics

Abstract

Objectives: Subarachnoid hemorrhage (SAH) may critically impair cardiovascular, metabolic, and gastrointestinal function. Previous research has demonstrated compromised drug absorption in this group of patients. This study aimed to examine the impact of SAH on gastrointestinal function and its subsequent effect on the absorption of enterally administered drugs, using esomeprazole as a probe drug.

Design: Prospective observational cohort study.

Setting: Academic hospital in Germany.

Patients: We included 17 patients with high-grade SAH and 17 controls, comparable in age, sex, body weight, and renal function, who underwent elective cranial surgery.

Interventions: None.

Measurements and main results: Both groups received esomeprazole per standard protocol to prevent acid-associated mucosal damage, either orally or through a nasogastric tube. On day 4, esomeprazole was administered IV to estimate oral bioavailability. Esomeprazole serum concentrations were measured on days 1, 3, and 4 in both groups and on day 7 in the SAH group. Patients with high-grade SAH exhibited severely impaired drug absorption. Most patients showed no improvement in intestinal drug absorption even a week after hemorrhage.

Conclusions: Following SAH, significantly reduced drug absorption may be attributed to decreased intestinal motility and compromised intestinal mucosal function. Clinicians should anticipate the reduced effectiveness of enterally administered medications for at least seven days after high-grade SAH.

Figure 1.

Design of the study on enteral absorption after subarachnoid hemorrhage (SAH). Study day 1 refers to day 1 or 2 after ictus in all patients. Each dose corresponds to esomeprazole administered once daily. In all patients with SAH who could not swallow, application (per os [po]) was performed via a nasogastric tube according to the manufacturer’s instructions. On day 1, control patients were in a stable state without major cardiovascular, gastrointestinal, or neuropsychiatric disabilities and could swallow the po dose. As studied earlier, the oral bioavailability of esomeprazole is almost identical if administered via a nasogastric tube or swallowed orally (17). PK = pharmacokinetic analysis.

Figure 2.

Means and 95% CIs of esomeprazole plasma concentrations in patients with high-grade subarachnoid hemorrhage (SAH) (blue) compared with patients admitted to the hospital for elective neurosurgery (green). On day 7, pharmacokinetic analysis was not performed in the control group. Instead, the control patients’ data from day 1 are compared here. At day 1, the control patients, being comparable concerning age and gender with the SAH patients, had normal intestinal and cardiovascular function, and the comparison of esomeprazole blood concentrations of the SAH patients at day 7 illustrates how severe their intestinal absorption impairment still was.

Figure 3.

Three primary metabolites of esomeprazole were analyzed as indicators of cytochrome P450 2C19 (5′-OH-esomeprazole and 5-O-desmethyl esomeprazole) and cytochrome P450 3A4 (esomeprazole sulfone) activity. Data are normalized for differences in bioavailability by the ratios of the respective metabolites over the parent drug. Blue boxes show the subarachnoid hemorrhage (SAH) group and green the control group. Medians are the horizontal lines in the boxes that show the 25th and 75th quartiles. Outliers are shown by open circles and far outliers by asterisks. There were no significant differences between the groups and study days concerning CYP2C19 activity. However, the esomeprazole sulfone formation was substantially lower in the SAH cohort indicating very low CYP3A enzyme activity.