Cytochrome P450 isozymes involved in lisofylline metabolism to pentoxifylline in human liver microsomes.
Article Details
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Lee SH, Slattery JT
Cytochrome P450 isozymes involved in lisofylline metabolism to pentoxifylline in human liver microsomes.
Drug Metab Dispos. 1997 Dec;25(12):1354-8.
- PubMed ID
- 9394024 [ View in PubMed]
- Abstract
We describe the kinetics of pentoxifylline formation from lisofylline in human liver microsomes using selective inhibitors of cytochrome P450 isozymes, correlation studies with specific isozyme activities, and cDNA-expressed human CYP1A2 and 2E1. A biphasic model fitted the data best for the formation of pentoxifylline, Km1 = 0.282 +/- 0.135 microM, Vmax1 = 0.003 +/- 0.001 nmol/min/mg protein, Km2 = 158 +/- 42.6 microM and Vmax2 =0.928 +/- 0.308 nmol/min/mg (N = 4). Pentoxifylline formation by the low Km isoform (200 microM lisofylline) required NADPH, was not inhibited by any isozyme-specific P450 inhibitor, and was inhibited only 10% and 20%, respectively, by aminobenzotriazole and N-octamylamine. We concluded that the low Km enzyme was not a cytochrome P450. At 5 microM of lisofylline the CYP1A2 inhibitor, furafylline, inhibited pentoxifylline formation by 58.8%, and the nonspecific CYP2E1 inhibitor, diethyldithiocarbamate, inhibited pentoxifylline formation by 21.7%. When preincubated with furafylline plus diethyldithiocarbamate, inhibition of pentoxifylline formation was increased 71.4%. Microsomal CYP1A2 activity correlated with pentoxifylline formation (r2 = 0.870, p < 0.001). However, CYP2E1 activity did not correlate with pentoxifylline formation (r2 = 0.143, p = 0.181). Baculovirus insect cell expressed human CYP1A2 formed pentoxifylline at 0.987 nmol/min/nmol cytochrome P450 at 5 microM lisofylline. cDNA expressed CYP2E1 did not catalyze formation of pentoxifylline. Diethyldithiocarbamate inhibited pentoxifylline formation by 85.7% in cDNA expressed CYP1A2. We conclude that CYP1A2 is the high affinity enzyme catalyzing pentoxifylline formation from lisofylline.
DrugBank Data that Cites this Article
- Drugs
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Lisofylline Cytochrome P450 1A2 Protein Humans NoSubstrateDetails Pentoxifylline Cytochrome P450 1A2 Protein Humans UnknownSubstrateDetails - Drug Reactions
Reaction Details - Drug Interactions
Drugs Interaction Integrate drug-drug
interactions in your softwarePentoxifyllineEnoxacin The serum concentration of Pentoxifylline can be increased when it is combined with Enoxacin. PentoxifyllineTechnetium Tc-99m ciprofloxacin The serum concentration of Pentoxifylline can be increased when it is combined with Technetium Tc-99m ciprofloxacin. PentoxifyllineClinafloxacin The serum concentration of Pentoxifylline can be increased when it is combined with Clinafloxacin. PentoxifyllineQuinidine The serum concentration of Pentoxifylline can be increased when it is combined with Quinidine. PentoxifyllineRofecoxib The serum concentration of Pentoxifylline can be increased when it is combined with Rofecoxib.
