Cytochrome P450 isozymes involved in lisofylline metabolism to pentoxifylline in human liver microsomes.

Article Details

Citation

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
DrugEnzymeKindOrganismPharmacological ActionActions
LisofyllineCytochrome P450 1A2ProteinHumans
No
Substrate
Details
PentoxifyllineCytochrome P450 1A2ProteinHumans
Unknown
Substrate
Details
Drug Reactions
Reaction
Details
Drug Interactions
DrugsInteraction
Pentoxifylline
Enoxacin
The serum concentration of Pentoxifylline can be increased when it is combined with Enoxacin.
Pentoxifylline
Technetium Tc-99m ciprofloxacin
The serum concentration of Pentoxifylline can be increased when it is combined with Technetium Tc-99m ciprofloxacin.
Pentoxifylline
Clinafloxacin
The serum concentration of Pentoxifylline can be increased when it is combined with Clinafloxacin.
Pentoxifylline
Quinidine
The serum concentration of Pentoxifylline can be increased when it is combined with Quinidine.
Pentoxifylline
Rofecoxib
The serum concentration of Pentoxifylline can be increased when it is combined with Rofecoxib.
Interactions
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