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A turnover model for irreversible inhibition of gastric acid secretion by omeprazole in gastric fistula dogs was developed using data from studies with both short- and long-term measurement periods. In the short-term experiments, after stimulation of acid secretion with histamine, the dogs were infused i.v. with omeprazole and acid secretion was measured for 5 h. Dose and infusion times were varied to produce different concentration-time profiles and schedule dependence in the inhibitory effect of omeprazole was observed. In the long-term experiments, dogs were given single intraduodenal doses, which inhibited the acid secretion for several days. Combining the short-term and long-term data allowed the observation of a biphasic recovery of acid secretion that was described by the turnover model. Second order association rate constants (k(ome)) for the covalent binding of omeprazole to H(+),K(+)-ATPase were estimated to 11 and 3.0 l/micromol/h for the i.v. and intraduodenal experiments, respectively. The apparent turnover rate constant of the enzyme (k(out)) was 0.013 h(-1) and the corresponding half-life of inhibition of acid secretory capacity was 54 h. The potency, calculated as k(out) over k(ome), was 4.3 and 1.2 nM for the intraduodenal and i.v. doses, respectively. Allometric scaling of the model resulted in trustworthy predictions for observations previously done in humans. The model predicted a good correlation between maximal inhibitory effect and exposure (area under the plasma concentration curve). The time dependence in this relation was also predicted by the model.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11046103&dopt=Abstract
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Drug Metab Dispos. 2001 Feb;29(2):133-40.
CYP3A4 is the major CYP isoform mediating the in vitro hydroxylation and demethylation of flunitrazepam.
Hesse LM, Venkatakrishnan K, von Moltke LL, Shader RI, Greenblatt DJ.
Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, 136 Harrison Ave., Boston, Massachusetts, USA.
The kinetics of flunitrazepam (FNTZ) N-demethylation to desmethylflunitrazepam (DM FNTZ), and 3-hydroxylation to 3-hydroxyflunitrazepam (3-OH FNTZ), were studied in human liver microsomes and in microsomes containing heterologously expressed individual human CYPs. FNTZ was N-demethylated by cDNA-expressed CYP2A6 (K(m) = 1921 microM), CYP2B6 (K(m) = 101 microM), CYP2C9 (K(m) = 50 microM), CYP2C19 (K(m) = 60 microM), and CYP3A4 (K(m) = 155 microM), and 3-hydroxylated by cDNA-expressed CYP2A6 (K(m) = 298 microM) and CYP3A4 (K(m) = 286 microM). The 3-hydroxylation pathway was predominant in liver microsomes, accounting for more than 80% of intrinsic clearance compared with the N-demethylation pathway. After adjusting for estimated relative abundance, CYP3A accounted for the majority of intrinsic clearance via both pathways. This finding was supported by chemical inhibition studies in human liver microsomes. Formation of 3-OH FNTZ was reduced to 10% or less of control values by ketoconazole (IC(50) = 0.11 microM) and ritonavir (IC(50) = 0.041 microM). Formation of DM FNTZ was inhibited to 40% of control velocity by 2.5 microM ketoconazole and to 30% of control by 2.5 microM ritonavir. Neither 3-OH FNTZ nor DM FNTZ formation was inhibited to less than 85% of control activity by alpha-naphthoflavone (CYP1A2), sulfaphenazole (CYP2C9), omeprazole (CYP2C19), or quinidine (CYP2D6). Thus, CYP-dependent FNTZ biotransformation, like that of many benzodiazepine derivatives, is mediated mainly by CYP3A. Clinical interactions of FNTZ with CYP3A inhibitors can be anticipated.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11159802&dopt=Abstract
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Gastroenterology. 1990 Dec;99(6):1576-80.
Human pepsinogen A isozymogen patterns in serum and gastric mucosa.
Zwiers A, Crusius B, Pals G, Donker AJ, Meuwissen SG, ten Kate RW.
Department of Internal Medicine, Free University Hospital, Amsterdam, The Netherlands.
The pepsinogen A isozymogen pattern in gastric mucosa is genetically determined and can be visualized in nondenaturating polyacrylamide gel electrophoresis of supernatants of sonified gastric mucosal biopsies by demonstrating proteolytic activity after converting pepsinogen into pepsin by acid. Pepsinogen isozymogens are present in very low concentrations in the blood but can now be demonstrated in serum by a newly developed immunoblotting procedure. This study investigated whether the serum pepsinogen A isozymogen pattern adequately reflects the pepsinogen A phenotype. Serum and gastric mucosal pepsinogen A isozymogen patterns were compared in 72 subjects from the routine endoscopy program. A close correlation was found between the relative intensities of the pepsinogen A isozymogens in the serum and the gastric mucosal patterns. Increasing the pepsinogen A release into the circulation by oral omeprazole did not affect the pepsinogen A patterns in the blood. It is concluded that the serum pepsinogen A pattern reflects the pepsinogen A phenotype in humans. In addition, no preferential release of a pepsinogen A isozymogen into the circulation was observed. Thus, immunoblotting of serum provides a new and reliable tool to study pepsinogen genetics in humans. Because a relationship was previously shown between specific pepsinogen A phenotypes and gastric malignancies in humans, serum pepsinogen A patterns may provide a tool to detect subjects who are at risk of gastric cancers.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2227273&dopt=Abstract
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