Prevacid
Oxidative metabolism of lansoprazole by human liver cytochromes P450.

Pichard L, Curi-Pedrosa R, Bonfils C, Jacqz-Aigrain E, Domergue J, Joyeux H, Cosme J, Guengerich FP, Maurel P.

INSERM U-128, CNRS, Montpellier, France.

The aim of this work was to identify the form(s) of human cytochrome P450 (P450) involved in the hepatic biotransformation of lansoprazole to its two main metabolites, i.e., the sulfone and the hydroxy derivative. In liver microsomes, the production of the sulfone of lansoprazole correlated with the level of P450 3A4, cyclosporin oxidase, and the production of the hydroxy derivative, as well as of omeprazole sulfone. The production of hydroxylansoprazole moderately correlated with the level of P450 3A4, cyclosporin oxidase, and (S)-mephenytoin 4'-hydroxylase. The production of the sulfone and of the hydroxy derivative of lansoprazole was significantly inhibited by anti-P450 3A4 antibodies, by cyclosporin and ketoconazole, and by tolbutamide. Anti-P450 2C8 and 2C3 antibodies moderately inhibited the biotransformation of lansoprazole, whereas they completely inhibited (S)-mephenytoin 4'-hydroxylase activity under the same conditions. In primary cultures of human hepatocytes, the biotransformation of lansoprazole and the oxidation of cyclosporin were strongly increased by rifampicin and phenobarbital, whereas (S)-mephenytoin 4'-hydroxylation was not. beta-Naphthoflavone did not induce the formation of the sulfones but stimulated the production of hydroxylansoprazole. Among several forms of cDNA-expressed human P450s, 3A4 generated significant amounts of the sulfones of lansoprazole and omeprazole and 2C18 was active for the production of hydroxylansoprazole but inactive in the 4'-hydroxylation of (S)-mephenytoin. We conclude that P450 3A4 is the major enzyme involved in the production of the sulfone of lansoprazole and that this P450, as well as P450 2C18 and/or another 2C-related form, could contribute to the production of hydroxylansoprazole.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7870052&dopt=Abstract lansoprazole Prevacid



Prevacid
Omeprazole and lansoprazole are mixed inducers of CYP1A and CYP3A in human hepatocytes in primary culture.

Curi-Pedrosa R, Daujat M, Pichard L, Ourlin JC, Clair P, Gervot L, Lesca P, Domergue J, Joyeux H, Fourtanier G, et al.

Institut National de la Sante et de la Recherche Medicale U-128, Centre National de la Recherche Scientifique, Montpellier, France.

The ability of several gastric antiulcer drugs including lansoprazole, cimetidine and ranitidine to affect the expression of human liver microsomal cytochromes P450 comparatively to omeprazole, reported previously to be a CYP1A inducer, was evaluated in primary cultures of human hepatocytes. Poly (A)+ RNA and microsomes extracted from the cells were analyzed in Northern and Western blots with specific cDNA probes and antibodies, and assayed for form-specific monoxygenase activities. Lansoprazole induced both CYP1A1 and CYP1A2 as omeprazole and did not apparently bind to the aryl hydrocarbon receptor with high affinity. Omeprazole sulfone was not an inducer of CYP1A. Omeprazole, omeprazole sulfone and lansoprazole induced CYP3A in approximately 50% of tested cultures, whereas 100% of tested cultures responded to omeprazole and to rifampicin in terms of CYP1A and CYP3A induction, respectively. Finally, cimetidine and ranitidine were not inducers. We conclude that omeprazole and lansoprazole constitute a new class of mixed inducers of CYP1A and CYP3A in human hepatocytes in primary culture and that the induction of CYP3A in response to these molecules could be polymorphic in humans.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8169844&dopt=Abstract lansoprazole Prevacid



Prevacid
[Dose-response effect of lansoprazole in patients with Zollinger-Ellison syndrome]

[Article in French]

Mignon M, Hochlaf S, Forestier S, Ruszniewski P, Vatier J, Joubert-Collin M.

Service d'Hepato-Gastroenterologie, CHU Bichat, Claude-Bernard, Universite Paris VII.

Lansoprazole, a new substituted benzimidazole, is an effective acid proton pump inhibitor acting by inhibiting selectively H+/K+ ATPase of the gastric parietal cell. This study was performed to assess the effect of successive 30, 60, 90 and 120 mg dosages of lansoprazole in 4 patients suffering from Zollinger-Ellison syndrome. The basal gastric acid output was markedly inhibited in comparison with baseline values (mean maximal reduction: 87%; extremes: 75-99%) and was dose-related. Lansoprazole inhibited pepsin output globally with a dose range effect between 30 and 90 mg/day. The treatment induced a rapid relief of clinical symptoms. No biological abnormality was noted. These data proved that lansoprazole is efficient for treating gastric acid hypersecretion in patients suffering from ZES.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8187984&dopt=Abstract lansoprazole Prevacid



Prevacid
Esomeprazole: a review of its use in the management of acid-related disorders in the US.

Scott LJ, Dunn CJ, Mallarkey G, Sharpe M.

Adis International Limited, 41 Centorian Drive, PB 65901, Mairangi Bay, Auckland 10, New Zealand. demail adis.co.nz

Esomeprazole, the S-isomer of omeprazole, is the first proton pump inhibitor to be developed as a single optical isomer. It provides better acid control than current racemic proton pump inhibitors and has a favourable pharmacokinetic profile relative to omeprazole. In large well designed 8-week trials in patients with erosive oesophagitis, esomeprazole recipients achieved significantly higher rates of endoscopically confirmed healed oesophagitis than those receiving omeprazole or lansoprazole. Esomeprazole was effective across all baseline grades of oesophagitis; notably, relative to lansoprazole, as the baseline severity of disease increased, the difference in rates of healed oesophagitis also increased in favour of esomeprazole. In two trials, 94% of patients receiving esomeprazole 40mg once daily achieved healed oesophagitis versus 84 to 87% of omeprazole recipients (20mg once daily). In a study in >5000 patients, respective healed oesophagitis rates with once-daily esomeprazole 40mg or lansoprazole 30mg were 92.6 and 88.8%. Resolution of heartburn was also significantly better with esomeprazole than with these racemic proton pump inhibitors. Long-term (up to 12 months) therapy with esomeprazole effectively maintained healed oesophagitis in these patients. Esomeprazole 20 or 40mg once daily for 4 weeks proved effective in patients with symptomatic gastro-oesophageal reflux disease (GORD) without oesophagitis. Eradicating Helicobacter pylori infection is considered pivotal to successfully managing duodenal ulcer disease. Ten days' triple therapy (esomeprazole 40mg once daily, plus twice-daily amoxicillin 1g and clarithromycin 500mg) eradicated H. pylori in 77 to 78% of patients (intention-to-treat) with endoscopically confirmed duodenal ulcer disease. Esomeprazole is generally well tolerated, both as monotherapy and in combination with antimicrobial agents. The tolerability profile is similar to that of other proton pump inhibitors. Few patients discontinued therapy because of treatment-emergent adverse events (<3% of patients) and very few (<1%) drug-related serious adverse events were reported. CONCLUSIONS: Esomeprazole is an effective and well tolerated treatment for managing GORD and for eradicating H. pylori infection in patients with duodenal ulcer disease. In 8-week double-blind trials, esomeprazole effectively healed oesophagitis and resolved symptoms in patients with endoscopically confirmed erosive oesophagitis. Notably, in large (n >1900 patients) double-blind trials, esomeprazole provided significantly better efficacy than omeprazole or lansoprazole in terms of both healing rates and resolution of symptoms. Long-term therapy with esomeprazole effectively maintained healed oesophagitis in these patients. Esomeprazole was also effective in patients with symptomatic GORD. Thus, esomeprazole has emerged as an effective option for first-line therapy in the management of acid-related disorders.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11985491&dopt=Abstract lansoprazole Prevacid



Prevacid
Pharmacokinetics of lansoprazole in patients with renal or liver disease of varying severity.

Delhotal-Landes B, Flouvat B, Duchier J, Molinie P, Dellatolas F, Lemaire M.

Toxicology and Pharmacokinetics Laboratory, Ambroise Pare Hospital, Boulogne-Billancourt, France.

The pharmacokinetics of lansoprazole (L) after a single oral dose of 30 mg was determined in 18 healthy volunteers, 17 renal failure patients and 24 hepatic failure patients; 8 hepatitis and 16 with compensated (CC) or uncompensated (UCC) cirrhosis. In renal failure, the absorption of L was unchanged, its half-life being similar to that in healthy subjects; a small change seen in mild renal failure patients (creatinine clearance between 40 and 60 ml/min) was attributed to the age of the patients. Urinary elimination, essentially as metabolites of lansoprazole, was decreased, in relation to the degree of renal impairment. In hepatitis patients, the AUC and t1/2 of L were doubled, without any change in Cmax. In cirrhotics tmax was prolonged, the AUC was increased (P < 0.001) and there was prolongation of t1/2 (6.1 h in CC and 7.2 h in UCC compared to 1.4 h in healthy subjects). These changes resulted from a decrease in the clearance of L. There was also an increase in its sulphone metabolite (Cmax, Rm) and a decrease in the hydroxylated metabolite (Cmax, Rm) in relation to the degree of liver disease, and reflecting a decrease in hydroxylation and biliary elimination. Thus, renal failure had no effect on the pharmacokinetics of L, but severe hepatic failure caused marked changes. A repeated dosing study would be necessary to evaluate the repercussions of the possible accumulation in cirrhotic patients.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8299672&dopt=Abstract lansoprazole Prevacid