Comparison of pantoprazole concentrations in simultaneous cerebrospinal fluid and serum samples

Abstract

Pantoprazole (PAN) is a proton pump inhibitor commonly used for gastro-esophageal reflux disease, but also for stress ulcer prophylaxis in ICU patients.

Central nervous system (CNS) adverse effects of PAN include nausea, vomiting, migraine headache and vertigo, suggesting that PAN may reach relevant concentrations in the CNS.

PAN is a substrate of the efflux transporters p-glycoprotein (Pgp, ABCB1) and breast cancer resistant protein (BCRP, ABCG2) which are located at the apical membrane of both the blood brain barrier (BBB) and the blood cerebrospinal fluid barrier (BCB).

There is evidence in rats that gastric proton pumps are expressed in the inner ear and in the epithelium of the choroid plexus (BCB), while it is unknown whether proton pumps are present in the CNS of humans.

Our aim was to examine the penetration of PAN into the CSF space
To investigate the permeability of the BCB for PAN in humans, we retrospectively quantified PAN concentrations by liquid chromatography/tandem mass spectrometry (LC-MS/MS) in serum and CSF samples withdrawn simultaneously (lower limit of quantification: 4.0 ng/ml for serum and 0.20 ng/ml for CSF).

Eleven CSF and 10 serum samples, respectively, were obtained from 10 neurological and 1 neurosurgical patients with thera-peutic administration of PAN prior to lumbar puncture. Relevant contamination with blood was ruled out microscopically, with only three of the CSF samples showing isolated erythrocytes.
The median concentration of PAN in CSF samples was 7.03 ng/ml (interquartile ranges 2.38-29.0 ng/ml), that of serum concentrations was 389 ng/ml (87.1-1112 ng/ml). CSF reached 2.22 % (1.58 – 4.47 %) of serum concentrations.
PAN can enter the CSF space but only to a minor extent.

Although PAN is a small sized molecule (389 Dalton molecular weight), its low lipophilicity (LogP=0.5) may explain the poor penetration. The efflux transporters Pgp and BCRP may reduce PAN penetration further. Even if proton pumps were expressed in the brain, local PAN concentrations would probably not be suffi-cient to explain CNS adverse effects by inhibition of such pumps.