Pantoprazole: Pantoprazole is enteric coated in Pantocid L so that absorption begins only after the capsule leaves the stomach. Peak serum concentration (Cmax) and area under the serum
concentration time curve (AUC) for enteric caoted pantoprazole increase in a manner proportional to
oral and intravenous doses from 10 mg to 80 mg. Pantoprazole does not accumulate, and its
pharmacokinetics are unaltered with multiple daily dosing. Following oral or intravenous
administration, the serum concentration of pantoprazole declines biexponentially, with a terminal
elimination half-life of approximately one hour.
In extensive metabolizers with normal liver function receiving an oral dose of the enteric-coated 40
mg pantoprazole tablet, the peak concentration (Cmax) is 2.5 μg/mL; the time to reach the peak
concentration (tmax) is 2.5 h, and the mean total area under the plasma concentration versus time
curve (AUC) is 4.8 μg•h/mL (range 1.4 to 13.3 μg•h/mL). Following intravenous administration of
pantoprazole to extensive metabolizers, its total clearance is 7.6-14.0 L/h, and its apparent volume of
distribution is 11.0-23.6 L.
After administration of a single or multiple oral 40 mg doses of pantoprazole delayed release tablets,
the peak plasma concentration of pantoprazole was achieved in approximately 2.5 hours, and Cmax
was 2.5 μg/mL. Pantoprazole undergoes little first-pass metabolism, resulting in an absolute
bioavailability of approximately 77%. Pantoprazole absorption is not affected by concomitant
administration of antacids.
Administration of pantoprazole delayed release tablets with food may delay its absorption up to 2
hours or longer; however, the Cmax and the extent of pantoprazole absorption (AUC) are not altered.
Thus, pantoprazole delayed release tablets may be taken without regard to timing of meals.
The apparent volume of distribution of pantoprazole is approximately 11.0-23.6 L, distributing mainly
in extracellular fluid. The serum protein binding of pantoprazole is about 98%, primarily to albumin.
Pantoprazole is extensively metabolized in the liver through the cytochrome P450 (CYP) system.
Pantoprazole metabolism is independent of the route of administration (intravenous or oral). The
main metabolic pathway is demethylation, by CYP2C19, with subsequent sulfation; other metabolic
pathways include oxidation by CYP3A4. There is no evidence that any of the pantoprazole
metabolites have significant pharmacologic activity.
After a single oral or intravenous dose of 14C-labeled pantoprazole to healthy, normal metabolizer
volunteers, approximately 71% of the dose was excreted in the urine, with 18% excreted in the feces
through biliary excretion. There was no renal excretion of unchanged pantoprazole.
Only slight to moderate increases in pantoprazole AUC (43%) and Cmax (26%) were found in elderly
volunteers (64 to 76 years of age) after repeated oral administration, compared with younger
subjects.
There is a modest increase in pantoprazole AUC and Cmax in women compared to men. However,
weight-normalized clearance values are similar in women and men. No dosage adjustment is
recommended based on gender.
In patients with severe renal impairment, pharmacokinetic parameters for pantoprazole were similar
to those of healthy subjects. No dosage adjustment is necessary in patients with renal impairment or
in patients undergoing hemodialysis.
In patients with mild to severe hepatic impairment (Child-Pugh A to C cirrhosis), maximum
pantoprazole concentrations increased only slightly (1.5-fold) relative to healthy subjects. Although
serum half-life values increased to 7-9 hours and AUC values increased by 5- to 7-fold in hepaticimpaired
patients, these increases were no greater than those observed in CYP2C19 poor
metabolizers, where no dosage adjustment is warranted. These pharmacokinetic changes in hepaticimpaired
patients result in minimal drug accumulation following once-daily, multiple-dose
administration. No dosage adjustment is needed in patients with mild to severe hepatic impairment.
Doses higher than 40 mg/day have not been studied in hepatically impaired patients.
Levosulpiride: The bioavailability of levosulpiride, when given orally is low (about 27% to 34%) with incomplete absorption as opposed to presystemic metabolism. Food reduces absorption by 30%.
Levosulpiride displays a protein binding of about 14% and a volume of distribution of 1 to 2.7 L/kg
which is similar in elderly and younger subjects.
Metabolism does not occur and the drug is excreted unchanged into the urine. The renal clearance is
15 to 30%. The drug is substantially excreted in the feces due to poor absorption. The lack of hepatic
metabolism makes metabolic interactions with cytochrome P-450 related substrates very unlikely.
