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• W2034001206 abstract "Abstract The aim of this study was to assess the interconversion pharmacokinetics and tissue distribution of pentoxifylline and the active ( R )‐enantiomer of its metabolite M1, lisofylline in male CD‐1 mice. Both compounds were administered intravenously at a dose of 50 mg/kg on two separate occasions. Serum and tissues were collected at different time points following drug administration. In addition, the ( S )‐enantiomer of M1 was administered to a group of mice and serum samples were obtained. Analyte concentrations were measured by chiral HPLC. All serum concentration versus time data were fitted simultaneously to a pharmacokinetic model incorporating interconversion processes of parent drug and metabolites. The estimated conversion clearance of (−)‐( R )‐M1 to pentoxifylline (CL 21 ) was six times greater than that for the reverse process (CL 12 ). The interconversion of pentoxifylline and (+)‐( S )‐M1 was faster as reflected by the values of conversion clearances CL 13 and CL 31 which were approximately 16 and 7 times greater in comparison with the corresponding clearances for the interconversion of pentoxifylline and (−)‐( R )‐M1. When fitting pharmacokinetic data of both parent compounds to a one‐compartment model, the values of elimination clearances assessed were close to those obtained on the basis of the interconversion model. After administration of pentoxifylline, tissue‐to‐serum AUC ratios ranged from 0.1 for liver and lungs to 0.32 for brain tissue. Serum levels of its metabolite, (−)‐( R )‐M1 were very low, whereas its tissue levels exceeded serum concentrations. The highest value of metabolite‐to‐parent AUC ratio (4.98) was observed in lungs. When (−)‐( R )‐M1 was given as a parent drug, tissue‐to‐serum AUC ratios in liver, kidney, and lungs were very close and ranged from 0.64 to 0.72. At the same time, levels of its metabolite, pentoxifylline were relatively low both in serum and all tissues studied. In consequence, metabolite‐to‐parent AUC ratios did not exceed the value of 0.27. In conclusion, reversible metabolism plays a modest role in the disposition of pentoxifylline and (−)‐( R )‐M1. It seems that pentoxifylline has less favourable pharmacokinetic properties than (−)‐( R )‐M1 due to lower concentrations attained in target organs. High levels of (−)‐( R )‐M1 observed after pentoxifylline administration in certain tissues such as liver or lungs suggest that pentoxifylline may constitute an effective prodrug for (−)‐( R )‐M1 in these organs. Chirality, 2006. © 2006 Wiley‐Liss, Inc." @default.
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• W2034001206 date "2006-01-01" @default.
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• W2034001206 title "Interconversion and tissue distribution of pentoxifylline and lisofylline in mice" @default.
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• W2034001206 doi "https://doi.org/10.1002/chir.20299" @default.
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