Relative contributions of CYP2C9 and 2C19 to phenytoin 4-hydroxylation in vitro: inhibition by sulfaphenazole, omeprazole, and ticlopidine. Regression of low-grade gastric mucosa-associated lymphoid tissue lymphoma after eradication of Helicobacter pylori: possible association with p16 hypermethylation. Role of CYP3A4 and CYP2C19 in the stereoselective metabolism of lansoprazole by human liver microsomes. Rx drugs

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Eur J Clin Pharmacol. 2001 Apr;57(1):31-6.
Relative contributions of CYP2C9 and 2C19 to phenytoin 4-hydroxylation in vitro: inhibition by sulfaphenazole, omeprazole, and ticlopidine.

Giancarlo GM, Venkatakrishnan K, Granda BW, von Moltke LL, Greenblatt DJ.

Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, 136 Harrison Ave., Boston, MA 02111, USA.

OBJECTIVES: To determine the relative contribution of cytochromes P450 (CYP) 2C9 and 2C19 to the formation of 5-(-4-hydroxyphenyl)-5-phenylhydantion (HPPH) from phenytoin (PPH). DESIGN: Hydroxylation of PPH to form HPPH was studied in vitro using human liver microsomes and microsomes from cDNA-transfected human lymphoblastoid cells. RESULTS: Formation of HPPH from PPH in liver microsomes had a mean (+/- SEM) apparent Km [substrate concentration corresponding to 50% of maximal reaction velocity (Vmax)] of 23.6 +/- 1.8 mumol/l. Coincubation with the CYP2C9 inhibitor, sulfaphenazole (SPA), at 5 mumol/l reduced reaction velocity to less than 15% of control values. The mean inhibitor concentration at which 50% inhibition is achieved (IC50 value) for SPA versus PPH hydroxylation (0.49 microM) was similar to the SPA IC50 versus flurbiprofen hydroxylation (0.46 microM) and tolbutamide hydroxylation (0.7-1.5 microM). In contrast, the CYP2C19 inhibitor omeprazole (OME) at 10 mumol/l produced only a small degree of inhibition. Incubation of PPH with microsomes from cDNA-transfected human lymphoblastoid cells containing CYP1A2, 2A6, 2B6, 2C8, 2D6, 2E1, or 3A4 yielded no detectable formation of HPPH. Only CYP2C9 and 2C19 had PPH hydroxylation activity, with apparent Km values for the high-affinity component of 14.6 mumol/l and 24.1 mumol/l, respectively. Based on Vmax values in liver microsomes, the Vmax and Km values in expressed CYPs and the relative abundance of the two isoforms in human liver, CYP2C9, and 2C19 were estimated to have relative contributions of 90% and 10%, respectively, to net intrinsic clearance. CONCLUSIONS: Formation of HPPH from PPH is mediated exclusively by CYP2C9 and 2C19, with CYP2C9 playing the major role.

online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11372587&dopt=Abstract

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J Gastroenterol. 2002 Jan;37(1):17-22.
Regression of low-grade gastric mucosa-associated lymphoid tissue lymphoma after eradication of Helicobacter pylori: possible association with p16 hypermethylation.

Kim YS, Kim JS, Jung HC, Lee CH, Kim CW, Song IS, Kim CY.

Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Korea.

BACKGROUND: Many reports have stated that the cure of Helicobacter pylori infection can induce a complete remission of low-grade gastric mucosa-associated lymphoid tissue (MALT) lymphoma. Although p16 hypermethylation was frequently found in MALT lymphoma, the association between this finding and the remission of MALT lymphoma has not been clarified. We performed a prospective study to evaluate the outcome of patients with low-grade gastric MALT lymphoma and the expression of p16 hypermethylation. METHODS: We prospectively enrolled 20 patients with H. pylori-positive low-grade gastric MALT lymphoma (stage I E1). After the eradication of H. pylori, the patients were regularly followed-up with endoscopic and histological assessment. The methylation-specific polymerase chain reaction (PCR) (MSP) method was used for the serial detection of p16 hypermethylation. RESULTS: Eighteen patients (90%) achieved complete remission, with a median duration of 15.7 months. The initial detection rate of p16 hypermethylation was 58% (7 of the 12 patients in whom p16 hypermethylation was evaluated successfully). In a serial investigation, 3 patients who were followed-up for a median 28 months showed that the p16 hypermethylation had disappeared. CONCLUSIONS: Complete remission of low-grade gastric MALT lymphoma after the eradication of H. pylori infection can be maintained for more than 1 year. Further studies are warranted to investigate the role of p16 hypermethylation in the pathogenesis of gastric MALT lymphoma.

online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11824795&dopt=Abstract

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Eur J Clin Pharmacol. 2001 Dec;57(10):709-15.
Role of CYP3A4 and CYP2C19 in the stereoselective metabolism of lansoprazole by human liver microsomes.

Katsuki H, Hamada A, Nakamura C, Arimori K, Nakano M.

Department of Pharmacy, Kumamoto University Hospital, Japan.

OBJECTIVE: The aim of this investigation was to clarify the stereoselective properties in lansoprazole metabolism by monitoring the metabolic consumption for each enantiomer and the formation of the main metabolites, lansoprazole sulfone and 5-hydroxylansoprazole, in the presence of human liver microsomal enzymes. METHODS: Human liver microsomes or recombinant cytochrome P450 (CYP) enzymes were incubated with either (+/- )-, (+)-, or (-)-lansoprazole in the presence of reduced nicotinamide adenine dinucleotide phosphate. The metabolic consumption of lansoprazole enantiomers was estimated from the amounts of enantiomers consumed by microsomal enzymes after incubation at 37 degrees C for 60 min. Metabolites of lansoprazole, lansoprazole sulfone, and 5-hydroxylansoprazole were determined after incubation at 37 degrees C for 20 min, and kinetic parameters [Michaelis constant (Km) and maximum velocity (Vmax)] were obtained using Eadie-Hofstee plots. RESULTS: (-)-Lansoprazole was metabolized more preferentially than (+)-lansoprazole in human liver microsomes. Stereoselective sulfoxidation and hydroxylation [(+) > (-)] were observed in human liver microsomes. Strikingly, in sulfoxidation, a significantly higher intrinsic clearance (Vmax,l/Km,l) of (-)-lansoprazole (0.023 +/- 0.001 ml/min/mg) than (+)-lansoprazole (0.006 +/- 0.000 ml/min/mg) was observed. Consequently, sulfoxidation is likely to play an important role in the stereoselective metabolism of lansoprazole enantiomers. P450-isoform specificity for each enantiomer was evident. CYP3A4, which mainly catalyzed sulfoxidation, was more active toward (-)-lansoprazole in either a chiral or racemic drug as a substrate. CYP2C19, which catalyzed hydroxylation, preferentially metabolized (+)-lansoprazole. The consumption of (+)-lansoprazole was markedly inhibited by (-)-lansoprazole, indicating a metabolic enantiomer/enantiomer interaction. However, this alteration of recombinant CYP2C19 specificity for (+)-lansoprazole did not appear in metabolism in human liver microsomes. CONCLUSIONS: Stereoselective metabolism was observed in human liver microsomes, and this stereoselectivity was mainly based on CYP3A4 specificity for preferable metabolism of (-)-lansoprazole.

online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11829200&dopt=Abstract

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