Prilosec online research references
Clin Pharmacol Ther. 1994 Apr;55(4):402-11.
Accelerated caffeine metabolism after omeprazole treatment is indicated by urinary metabolite ratios: coincidence with plasma clearance and breath test.
Rost KL, Roots I.
Institute of Clinical Pharmacology, Klinikum Steglitz, Free University of Berlin, Germany.
BACKGROUND: Omeprazole has previously been shown to induce hepatic cytochrome P4501A2 activity, as evidenced by an accelerated N-3-demethylation in the 13C-[N-3-methyl]-caffeine breath test. In this study we investigated whether the inducing potency of omeprazole can be quantified by the determination of urinary caffeine metabolite ratios, which are based on the urinary excretion of N-3-demethylated metabolites. These data were also compared with changes in plasma clearance. METHODS: Twelve healthy volunteers were phenotyped as extensive metabolizers of S-mephenytoin and received seven daily doses of 40 mg omeprazole; eight of these were also treated with 120 mg/day. Moreover, six poor metabolizers were treated with 40 mg/day omeprazole. Three different urinary caffeine metabolite ratios were evaluated from urine samples collected between 5 and 8 hours after caffeine intake. RESULTS: The extensive metabolizers had a slight and nonsignificant acceleration between 7.8% and 17.0% after 40 mg omeprazole by the urinary ratios. However, treatment with 120 mg/day led to highly significant increases ranging from 25.0% to 32.1% (p < 0.002) in this group. Poor metabolizers responded with the highest increases of 40.2% to 41.2%. There was a good correlation between these parameters and the caffeine breath test, as well as the plasma caffeine clearance. CONCLUSION: The study showed an equivalent caffeine N-3-demethylation activity by all evaluation methods. The three urinary caffeine metabolite ratios sampled at the convenient interval of 5 to 8 hours after administration showed the dependence of CYP1A2 induction by omeprazole on the dose and genetic trait of S-mephenytoin hydroxylase.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8162667&dopt=Abstract
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1. The inhibitory effects of cimetidine, nizatidine and omeprazole on the metabolic activity of CYP2C9, 2C19, 2D6 and 3A were investigated in human liver microsomes. Both cimetidine and omeprazole inhibited each of the CYP subfamily enzymes; in particular, omeprazole extensively inhibited the hydroxylation of S-mephenytoin (CYP2C19, Ki = 7.1 microM). Nizatidine exhibited no inhibition of any of the CYP isoforms examined. 2. Cimetidine inhibited the hydroxylation of tolbutamide but not of diclofenac, whereas omeprazole inhibited the hydroxylation of diclofenac but not that of tolbutamide. The ability to inhibit CYP2C9 varied with incubation time, as measured by the metabolic rate constant for the substrates. Therefore, suitable substrates and incubation times must be selected in inhibition studies examining metabolic clearance and the mechanism of inhibition of these drugs. 3. Nizatidine did not inhibit the metabolism of cisapride, glibenclamide, benidipine and simvastatin. Omeprazole inhibited the metabolism of cisapride (Ki = 0.4 microM), glibenclamide (11.7 microM) and benidipine (6.5 microM), whereas cimetidine inhibited the metabolism of glibenclamide (11.6 microM). To avoid drug-drug interactions, care needs to be taken to select suitable medicines for co-administration with anti-ulcer drugs.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11334262&dopt=Abstract
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J Hepatol. 1995 Sep;23(3):268-77.
Phenocopies of poor metabolizers of omeprazole caused by liver disease and drug treatment.
Rost KL, Brockmoller J, Esdorn F, Roots I.
Institute of Clinical Pharmacology, Universitatsklinikum Benjamin Franklin, Berlin, Germany.
BACKGROUND/AIMS: The kinetics of omeprazole and its primary metabolites 5'-hydroxyomeprazole and omeprazole sulfone were studied in healthy volunteers to evaluate omeprazole as a probe drug for the S-mephenytoin hydroxylase (CYP2C19) polymorphism. The plasma metabolic ratio obtained from the concentrations of omeprazole plus omeprazole sulfone over 5'-hydroxyomeprazole was investigated. METHODS: The time course of the omeprazole metabolic ratio was studied in 14 extensive metabolizers, one intermediate, and five poor metabolizers of CYP2C19 after a 1-week administration of 40 mg/d omeprazole. The ratio was then determined in 187 randomly selected Caucasian hospital patients and analyzed according to liver disease and co-medication. RESULTS: Between 1 and 4 h after omeprazole intake, the volunteers phenotyped by the urinary S/R-mephenytoin ratio were reliably identified as extensive metabolizers and poor metabolizers by an omeprazole metabolic ratio-antimode of 12. This antimode remained valid in eight extensive metabolizers and one poor metabolizer, who were re-investigated with 60 mg omeprazole b.i.d. for one week. Among 30 patients without concomitant drug intake, only one poor metabolizer (3.3%) was identified by both the S/R-mephenytoin ratio and omeprazole metabolic ratio. However, 30 of 47 patients with liver disease and 20 of 110 co-medicated patients without liver disease had a ratio > 12. This highly exceeded the poor metabolizer frequency of 3-4% in Caucasians. CONCLUSIONS: Like other phenotypic tests, the omeprazole metabolic ratio appears to reflect CYP2C19 genotype reliably only in individuals without liver disease or co-medication. The omeprazole metabolic ratio may serve the double purpose of phenotyping for CYP2C19 and to individualize dosing in omeprazole-treated patients.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8550990&dopt=Abstract
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J Pharmacol Exp Ther. 1992 Sep;262(3):1195-202.
Disposition kinetics and metabolism of omeprazole in extensive and poor metabolizers of S-mephenytoin 4'-hydroxylation recruited from an Oriental population.
Sohn DR, Kobayashi K, Chiba K, Lee KH, Shin SG, Ishizaki T.
Department of Pharmacology, College of Medicine, Gyeongsang National University, Chinju, Korea.
To explore the relationship between omeprazole disposition and genetically determined S-mephenytoin 4'-hydroxylation phenotype status, we examined the kinetic variables of omeprazole and its two primary metabolites in plasma (5-hydroxyomeprazole and omeprazole sulfone) and the excretion profile of its principal metabolite in urine (5-hydroxyomeprazole) in eight extensive (EMs) and eight poor metabolizers (PMs) recruited from a Korean population. Each subject received a p.o. dose of 20 mg of omeprazole as an enteric-coated formulation, and blood and urine samples were collected up to 24 hr postdose. Omeprazole and its metabolites were measured by high-performance liquid chromatography with ultraviolet detection. The mean omeprazole area under the concentration-time curve (AUC), elimination half-life (T1/2) and apparent p.o. clearance were significantly (P less than .001) greater, longer and lower, respectively, in PMs than in EMs. The mean peak concentration and AUC of 5-hydroxyomeprazole and AUC ratio of 5-hydroxyomeprazole to omeprazole were significantly (P less than .01 to .001) less in PMs than in EMs. The mean peak plasma concentration, AUC of omeprazole sulfone and ratio of omeprazole sulfone to omeprazole were greater (P less than .001) and T1/2 was longer (P less than .001) in PMs than in EMs. The mean cumulative urinary excretion of 5-hydroxyomeprazole up to 24 hr postdose was significantly (P less than .001) less in PMs than in EMs. In addition, the log10 4'-hydroxymephenytoin excreted in urine correlated significantly (P less than .01) with the apparent p.o. clearance of omeprazole and half-lives of omeprazole, 5-hydroxyomeprazole and omeprazole sulfone.(ABSTRACT TRUNCATED AT 250 WORDS)
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1527724&dopt=Abstract
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Pharmacol Toxicol. 1997 Dec;81(6):247-52.
Lansoprazole and ethanol metabolism: comparison with omeprazole and cimetidine.
Battiston L, Tulissi P, Moretti M, Pozzato G.
Institute of Clinical Medicine, University of Trieste, Italy.
Since some antisecretory drugs such as cimetidine and ranitidine, interfere with ethanol metabolism by inhibition of hepatic and/or gastric alcohol dehydrogenase, we investigated the effect of lansoprazole, a new protonic pump inhibitor, on gastric and hepatic alcohol dehydrogenase activity. We also compared the lansoprazole effect with that of omeprazole and cimetidine, respectively. Ethanol blood concentration after oral intake or intravenous administration of ethanol was estimated either in normal male human volunteers or in male rats before and after one week pretreatment with lansoprazole, omeprazole and cimetidine. Furthermore, the in vitro effect of these drugs was studied on both human and rat gastric and hepatic alcohol dehydrogenases. Finally, we measured the effect of the treatment on the reduced hepatic glutathione to test the effects of the drugs on first-pass metabolism of ethanol. The results reported in this paper indicate that lansoprazole, as well as omeprazole, does not affect ethanol metabolism, and that protonic pump inhibitors seem to be safer than imidazole-derived drugs in subjects unable to reduce ethanol intake during conditions requiring acid secretion inhibition.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9444664&dopt=Abstract
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