Drugs online research references
Br J Clin Pharmacol. 1993 Dec;36(6):521-30.
Identification of human liver cytochrome P450 isoforms mediating omeprazole metabolism.
Andersson T, Miners JO, Veronese ME, Tassaneeyakul W, Tassaneeyakul W, Meyer UA, Birkett DJ.
Clinical Pharmacology, Astra Hassle AB, S-43183 Molndal, Sweden.
1 The in vitro metabolism of omeprazole was studied in human liver microsomes in order to define the metabolic pathways and identify the cytochrome P450 (CYP) isoforms responsible for the formation of the major omeprazole metabolites. 2 The four major metabolites identified in vitro, in tentative order of importance, were hydroxyomeprazole, omeprazole sulphone, 5-O-desmethylomeprazole, and an unidentified compound termed metabolite X. Omeprazole pyridone was also detected but could not be quantitated. Incubation of hydroxyomeprazole and omeprazole sulphone with human microsomes resulted in both cases in formation of the hydroxysulphone. The kinetics of formation of the four primary metabolites studied were biphasic suggesting the involvement of multiple CYP isoforms in each case. Further studies used substrate concentrations at which the high affinity activities predominated. 3 Formation of the major metabolite, hydroxyomeprazole, was significantly correlated with S-mephenytoin hydroxylase and with benzo[a]pyrene metabolism and CYP3A content. Inhibition studies with isoform selective inhibitors also indicated a dominant role of S-mephenytoin hydroxylase with some CYP3A contribution in the formation of hydroxyomeprazole. Correlation and inhibition data for the sulphone and metabolite X were consistent with a predominant role of the CYP3A subfamily in formation of these metabolites. Formation of 5-O-desmethylomeprazole was inhibited by both R, S-mephenytoin and quinidine, indicating that both S-mephenytoin hydroxylase and CYP2D6 may mediate this reaction in human liver microsomes and in vivo. 4 The Vmax/Km (indicator of intrinsic clearance in vivo) for hydroxyomeprazole was four times greater than that for omeprazole sulphone. Consistent with findings in vivo, the results predict that omeprazole clearance in vivo would be reduced in poor metabolisers of mephenytoin due to reduction in the dominant partial metabolic clearance to hydroxyomeprazole.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12959268&dopt=Abstract
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Br J Clin Pharmacol. 1993 Nov;36(5):467-9.
Single and multiple dose pharmacokinetics of lansoprazole in elderly subjects.
Flouvat B, Delhotal-Landes B, Cournot A, Dellatolas F.
Toxicology and Pharmacokinetics Laboratory, AMBROISE PARE Hospital, 92100 Boulogne-Billancourt, France.
Plasma concentrations of lansoprazole and of its sulphone, sulphide and 5-hydroxylated metabolites were determined after oral administration of a single 30 mg dose and after 7 days of treatment with a daily 30 mg dose in 12 elderly subjects (mean age 83 years). Results after a single dose were compared with those from a historical control group of 18 young subjects (mean age 23 years). Mean values of AUC after single dose were 2668 ng ml(-1) h in the young subjects and 5216 ng ml(-1) h in the elderly (P < 0.05). Mean t 1/2z values in young and elderly subjects were 1.4 h and 2.9 h, respectively (P < 0.001). Plasma concentrations of the metabolites were similar in both groups. However, the hydroxylated metabolite of the sulphone was detected only in elderly subjects. Steady state plasma concentrations of lansoprazole were reached after 3 days of dosing with lansoprazole. The accumulation ratio was 1.31 in the elderly subjects.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12959297&dopt=Abstract
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Br J Clin Pharmacol. 1993 Oct;36(4):380-2.
Absence of an inhibitory effect of omeprazole and nizatidine on phenytoin disposition, a marker of CYP2C activity.
Bachmann KA, Sullivan TJ, Jauregui L, Reese JH, Miller K, Levine L.
The Center for Applied Pharmacology, The University of Toledo College of Pharmacy, Toledo, Ohio 43606, USA.
The effects of omeprazole (40 mg orally per day) and nizatidine (300 mg orally per day) on the disposition of phenytoin (4.5 mg kg(-1) p.o. single dose) were studied in 18 healthy, young adult males. Total and unbound plasma concentrations of phenytoin were measured for 48 h after each dose of phenytoin. Neither treatment altered the disposition kinetics of phenytoin, the hydroxylation of which is mediated specifically by cytochromes P450 of the 2C subfamily.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12959321&dopt=Abstract
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