Comparison of pantoprazole concentrations in

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Comparison of pantoprazole concentrations in simultaneous cerebrospinal fluid and serum samples Sigaroudi A2, Stelzer C1, Braun T1, Schröter M4, Kinzig M1, Fuhr U2, Holzgrabe U3, Sörgel F1 1Institute for Biomedical and Pharmaceutical Research, Nürnberg-Heroldsberg, Germany; 2Department of Pharmacology, Cologne University Hospital, Germany; 3Institute of Pharmacy and Food Chemistry, University of Würzburg, Germany; 4Department of Neurology, Cologne University Hospital, Germany Background & Objectives PatNo. Age Cserum (ng/ml) Ccsf Ratio of CSF/Serum Qalbumin hours between PAN and LP 1 73 NS 43.3 NA 8.6 03h35min 2 18 1260 28.1 0.02 3.3 01h7min 3 61 2297 15.3 06h40min 4 60 12.9 2.43 0.19 18.6 15h55min 5 47 667 29.9 0.04 26.8 06h1min 73.9 2.33 0.03 17h32min 6 37 126 2.00 21h25min 7 65 06h7min 8 9204 136 0.01 8.5 02h46min 9 27 8.96 1.41 0.16 16.3 0h54min 10 71 290 5.65 2.9 07h60min 11 55 488 7.03 7.7 17h28min 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 Table: Serum and CSF concentrations of PAN in paired samples Legend: Qalbumin= quotient of albumin (concentration of albumin in CSF/conc. of albumin in serum); C=concentration; NS=:no sample; NA: not applicable; LP: lumbar puncture; PAN: pantoprazole Methods Patients & Data 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quantified PAN concentrations by liquid chromatography/tandem mass spectrometry (LC-MS/MS) in serum and CSF samples withdrawn simultaneously (lower limit of quantification: 4.0 ng/ml for serum and 0.20 ng/ml for CSF).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. Results 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. Conclusion 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. Figures : point charts of serum (top) and cerebrospinal fluid (bottom) concentrations of pantoprazole in paired samples (note the different scales) Legend: Concentration of pantoprazole in serum Concentration of pantoprazole In cerebrospinal fluid References Lecain E et al. Hear Res (2000) 149(1-2):157-154.