Pharmacology: Pharmacodynamics: Aceclofenac: Aceclofenac is a nonsteroidal agent with marked anti-inflammatory and analgesic properties. The mode of action of aceclofenac is largely based on the inhibition of prostaglandin synthesis. Aceclofenac is a potent inhibition of the enzyme cyclooxygenase, which is involved in the production of prostaglandins.
Rabeprazole: Rabeprazole sodium belongs to the class of antisecretory compounds, the substituted benzimidazoles, that do not exhibit anticholinergic or H2-histamine antagonist properties, but suppress gastric acid secretion by the specific inhibition of the H+/K+-ATPase enzyme (the acid or proton pump). The effect is dose-related and leads to inhibition of both basal and stimulated acid secretion, irrespective of the stimulus. Animal studies indicate that after administration, rabeprazole sodium rapidly disappears from both the plasma and gastric mucosa. As a weak base, rabeprazole is rapidly absorbed following all doses and is concentrated in the acid environment of the parietal cells. Rabeprazole is converted to the active sulphenamide form through protonation and it subsequently reacts with the available cysteines on the proton pump.
After oral administration of rabeprazole sodium 20 mg, the onset of the antisecretory effect occurs within 1 hr, with the maximum effect occurring within 2-4 hrs. Inhibition of basal and food stimulated acid secretion 23 hrs after the first dose of rabeprazole sodium are 69% and 82%, respectively, and the duration of inhibition lasts up to 48 hrs. The inhibition effect of rabeprazole sodium on acid secretion increases slightly with repeated once-daily dosing, achieving steady state inhibition after 3 days. When the drug is discontinued, secretory activity normalizes over 2-3 days.
Pharmacokinetics: Aceclofenac: After oral administration, aceclofenac is rapidly and completely absorbed as unchanged drug. Peak plasma concentrations are reached approximately 1.25-3 hrs following ingestion. Aceclofenac penetrates into the synovial fluid, where the concentrations reach approximately 57% of those in plasma. The volume of distribution is approximately 25 L. The mean plasma elimination half-life (t½) is around 4 hrs. Aceclofenac is highly protein-bound (>99%). Aceclofenac circulates mainly as unchanged drug. 4'-Hydroxyaceclofenac dose is excreted via urine, mainly as hydroxymetabolites. No changes in the pharmacokinetics of aceclofenac have been detected in the elderly.
Rabeprazole: Rabeprazole is an enteric-coated (gastro-resistant) formulation of rabeprazole sodium. This presentation is necessary because rabeprazole is acid-labile. Absorption of rabeprazole therefore begins only after it leaves the stomach. Absorption is rapid, with peak plasma levels of rabeprazole occurring approximately 3.5 hrs after a 20 mg dose. Peak plasma concentrations (Cmax) of rabeprazole and AUC are linear over the dose range of 10-40 mg. Absolute bioavailability of an oral 20-mg dose (compared to IV administration) is about 52% due in large part to presystem metabolism. Additionally, the bioavailability does not appear to increase with repeat administration. In healthy subjects, the plasma t½ is approximately 1 hr (range 0.7-1.5 hrs), 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 the day of administration of the treatment affect the absorption of rabeprazole sodium.
Rabeprazole is approximately 97% bound to human plasma proteins.
Rabeprazole sodium, as is the case with other members of the proton-pump inhibitor (PPI) class of compounds, is metabolized though the cytochrome P450 (CVP45q) hepatic drug metabolising 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 conjugates (M5) minor metabolites observed at lower levels. Only the desmethyl metabolite (M3) has a small amount of antisecretory activity, butitis not present in plasma.
Following a single 20 mg 14C labelled oral dose of rabeprazole sodium, no unchanged drugs was excreted in the urine. Approximately, 90% of the dose was eliminated in urine mainly as the 2 metabolites: A mercapturic acid conjugate (M5) and a carboxylic acid (M6), plus 2 unknown metabolites. The remainder of the dose was recovered in faeces.
Special Populations: Geriatrics: Aceclofenac: Maximum plasma concentrations (Cmax) of aceclofenac and times to Cmax (Tmax) are similar after single (100 mg) and multiple (100 mg twice daily for 7 days). Oral doses: In a study in 12 elderly volunteers, mean Cmax values ranged from 8.94-9.86 mg/mL and were achieved in 1.08-1.37 hrs. Areas under plasma drug concentration versus time curves (AUCs) were increased over those seen after single doses in young individuals and decreased in the elderly after multiple doses. No significant differences were observed between young and elderly volunteers in Cmax absorption t½ or V4 values.
Rabeprazole: Elimination of rabeprazole was somewhat decreased in the elderly. Following 7 days of daily dosing with rabeprazole sodium 20 mg, the AUC approximately doubled, the Cmax increased by 60% and t½ increased by approximately 30% as compared to young healthy volunteers. However, there was no evidence of rabeprazole accumulation.
Gender: Rabeprazole: Adjusted for body mass and height, there are no significant gender differences in pharmacokinetic parameters following a single dose of rabeprazole 20 mg.
Renal Dysfunction: Rabeprazole: In as reported study, patients with stable, end-stage, renal failure requiring maintenance haemodialysis [creatinine clearance (CrCl) 5 mL/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 t½ of rabeprazole was 0.82 hrs in healthy volunteers, 0.95 hrs in patients during haemodialysis and 3.6 hrs post-dialysis. The clearance of the drug in patients was approximately twice that in healthy volunteers.
Hepatic Dysfunction: Rabeprazole: Following a single dose of rabeprazole 20 mg to patients with chronic mild to moderate hepatic impairment the AUC doubled and there was a 2- to 3-fold increase in t½ 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 t½ of rabeprazole in patients with hepatic impairment was 12.3 hrs compared to 2.1 hrs in healthy volunteers. The pharmacodynamic response (gastric pH control) in the 2 groups was clinically comparable.
Rabeprazole: Following a dose of rabeprazole 20 mg for 7 days, CYP2C19 slow metabolizes, had AUC and t½ which were approximately 1.9 and 1.6 times the corresponding parameters in extensive metabolizes whilst Cmax had increased only 40%.