Pharmacokinetics

Absorption Distribution Metabolism Excretion Special Population Other Details

Absorption

Rabeprazole sodium (PARIET®) is an enteric-coated (gastro-resistant) tablet formulation of rabeprazole sodium. This presentation is necessary because rabeprazole is acid-labile. Absorption of rabeprazole therefore begins only after the tablet leaves the stomach. Absorption is rapid, with peak plasma levels of rabeprazole occurring approximately 3.5 hours after a 20 mg dose. Peak plasma concentrations (Cmax) of rabeprazole and AUC are linear over the dose range of 10 mg to 40 mg. Absolute bioavailability of an oral 20 mg dose (compared to intravenous administration) is about 52% due in large part to pre-systemic metabolism. Additionally the bioavailability does not appear to increase with repeat administration. In healthy subjects the plasma half-life is approximately one hour (range 0.7 to 1.5 hours), and the total body clearance is estimated to be 283 ± 98 mL/min. There was no clinically relevant interaction with food. Neither food nor the time of day of administration of the treatment affect the absorption of rabeprazole sodium.


Distribution

Rabeprazole is approximately 97% bound to human plasma proteins.


Metabolism

Rabeprazole sodium, as is the case with other members of the proton pump inhibitor (PPI) class of compounds, is metabolised through the cytochrome P450 (CYP450) hepatic drug metabolizing system. In vitro studies with human liver microsomes indicated that rabeprazole sodium is metabolised by isoenzymes of CYP450 (CYP2C19 and CYP3A4). In these studies, at expected human plasma concentrations rabeprazole neither induces nor inhibits CYP3A4; and although in vitro studies may not always be predictive of in vivo status these findings indicate that no interaction is expected between rabeprazole and cyclosporin. In humans the thioether (M1) and carboxylic acid (M6) are the main plasma metabolites with the sulphone (M2), desmethyl-thioether (M4) and mercapturic acid conjugate (M5) minor metabolites observed at lower levels. Only the desmethyl metabolite (M3) has a small amount of anti-secretory activity, but it is not present in plasma.


Excretion

Following a single 20 mg 14C labeled oral dose of rabeprazole sodium, no unchanged drug was excreted in the urine. Approximately 90% of the dose was eliminated in urine mainly as the two metabolites: a mercapturic acid conjugate (M5) and a carboxylic acid (M6), plus two unknown metabolites. The remainder of the dose was recovered in feces.


Special Population

Renal dysfunction: In patients with stable, end-stage renal failure requiring maintenance hemodialysis (creatinine clearance ≤5mL/min/1 .73m2) the disposition of rabeprazole was very similar to that in healthy volunteers. The AUC and the Cmax in these patients was about 35% lower than the corresponding parameters in healthy volunteers. The mean half-life of rabeprazole was 0.82 hours in healthy volunteers, 0.95 hours in patients during hemodialysis and 3.6 hours post dialysis. The clearance of the drug In patients with renal disease requiring maintenance hemodialysis was approximately twice that in healthy volunteers.

Hepatic dysfunction: Following a single 20 mg dose of rabeprazole to patients with chronic mild to moderate hepatic impairment the AUC doubled and there was a 2-3 fold increase in half-life of rabeprazole compared to the healthy volunteers. However, following a 20 mg dose daily for 7 days the AUC had increased to only 1.5-fold and the Cmax to only 1.2-fold. The half-life of rabeprazole in patients with hepatic impairment was 12.3 hours compared to 2.1 hours in healthy volunteers. The pharmacodynamic response (gastric pH control) in the two groups was clinically comparable.

Elderly: Elimination of rabeprazole was somewhat decreased in the elderly Following 7 days of daily dosing with 20 mg of rabeprazole sodium, the AUC approximately doubled, the Cmax increased by 60% and t1/2 increased by approximately 30% as compared to young healthy volunteers. However, there was no evidence of rabeprazole accumulation.


Other details

Gender: Adjusted for body mass and height, there are no significant gender differences in pharmacokinetic parameters following a single 20 mg dose of rabeprazole.

CYP2C19 Polymorphism: Following a 20 mg daily dose of rabeprazole for 7 days, CYP2C19 slow metabolizers, had AUC and t1/2 which were approximately 1.9 and 1.6 times the corresponding parameters in extensive metabolizers whilst Cmax had increased by only 40%.