Effect of phenytoin on meperidine clearance and normeperidine formation

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Abstract
The presystemic metabolism of meperidine to normeperidine was examined in 4 healthy men before, during and 3 wk after phenytoin. The results from the 2 control periods were similar. Meperidine systemic clearance rose from 1017 .+-. 225 ml/min to 1280 .+-. 130 ml/min during phenytoin dosing (P < 0.01). Meperidine elimination half-life fell from 6.4 .+-. 1.0 h to 4.3 .+-. 0.4 h during phenytoin dosing (P < 0.05). Bioavailability fell from 0.61 .+-. 0.08 to 0.43 .+-. 0.14 (P < 0.07). Meperidine volume of distribution, renal clearance and protein binding did not change. The normeperidine area under the blood concentration-time curve from 0-24 h after i.v. meperidine rose from 385 .+-. 105 ng/h per ml-1 to 589 .+-. 108 ng/h per ml-1 during phenytoin dosing (P < 0.01); after oral meperidine it rose from 592 .+-. 50 ng/h per ml-1 to 738 .+-. 176 ng/h per ml-1. Normeperidine renal clearance was .apprx. 4 times that of meperidine, but was not altered by phenytoin. Because analgesia relates to meperidine blood concentrations, patients on long-term phenytoin therapy may require more frequent parenteral doses and larger and more frequent oral doses than usual.