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Effect of phenytoin on meperidine clearance and normeperidine formation
Abstract:
The presystemic metabolism of meperidine to normeperidine was examined in four healthy men before, during, and 3 wk after phenytoin. The results from the two control periods were similar. Meperidine systemic clearance rose from 1017 +/- 225 ml/min (mean +/- SD) to 1280 +/- 130 ml/min during phenytoin dosing (P less than 0.01). Meperidine elimination half-life fell from 6.4 +/- 1.0 hr to 4.3 +/- 0.4 hr during phenytoin dosing (P less than 0.05). Bioavailability fell from 0.61 +/- 0.08 to 0.43 +/- 0.14 (P less than 0.07). Meperidine volume of distribution, renal clearance, and protein binding did not change. The normeperdine area under the blood concentration-time curve from 0 to 24 hr after intravenous meperidine rose from 385 +/- 105 ng/hr/ml-1 to 589 +/- 108 ng/hr/ml-1 during phenytoin dosing (P less than 0.01); after oral meperidine it rose from 592 +/- 50 ng/hr/ml-1 to 738 +/- 178 ng/hr/ml-1. Normeperidine renal clearance was approximately four 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.
Insights
Phenytoin significantly alters meperidine metabolism in healthy men, increasing its clearance and reducing its half-life and bioavailability. This drug interaction may necessitate dose adjustments for patients receiving both medications.
Area of Science:
- Pharmacology
- Drug Metabolism
- Clinical Pharmacology
Background:
- Meperidine is an opioid analgesic metabolized to normeperidine.
- Phenytoin is an anticonvulsant known to induce drug-metabolizing enzymes.
Purpose of the Study:
- To investigate the effect of phenytoin on the presystemic metabolism of meperidine to normeperidine in healthy men.
Main Methods:
- Four healthy men received meperidine (both intravenous and oral) before, during, and after a course of phenytoin.
- Pharmacokinetic parameters including systemic clearance, elimination half-life, bioavailability, and metabolite concentrations were measured.
Main Results:
- Phenytoin increased meperidine systemic clearance (P < 0.01) and decreased its elimination half-life (P < 0.05).
- Meperidine bioavailability decreased during phenytoin administration (P < 0.07).
- Normeperidine exposure (area under the curve) increased significantly after both intravenous and oral meperidine during phenytoin therapy (P < 0.01).
Conclusions:
- Phenytoin significantly enhances meperidine metabolism, leading to increased normeperidine formation.
- Patients on long-term phenytoin therapy may require adjusted meperidine dosing strategies to maintain analgesia.