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Influence of debrisoquin phenotype on the inducibility of propranolol metabolism

O Shaheen1, J Biollaz, R P Koshakji

  • 1Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232.

Clinical Pharmacology and Therapeutics
|April 1, 1989
PubMed

Insights

Rifampin significantly increased propranolol clearance in both extensive metabolizers (EMs) and poor metabolizers (PMs). However, the induction of 4-hydroxylation, a key metabolic pathway, was substantially greater in EMs.

Area of Science:

  • Pharmacology
  • Drug Metabolism
  • Genetics

Background:

  • Propranolol is extensively metabolized by cytochrome P450 enzymes.
  • Genetic variations in debrisoquin metabolism define extensive metabolizers (EMs) and poor metabolizers (PMs), impacting drug clearance.
  • Rifampin is a known inducer of drug-metabolizing enzymes.

Purpose of the Study:

  • To investigate the effects of rifampin on the metabolic clearance of propranolol in EMs and PMs.
  • To determine the impact of rifampin on specific propranolol metabolic pathways, including 4-hydroxylation and glucuronidation.

Main Methods:

  • A study involving six EMs and six PMs of debrisoquin.
  • Administration of rifampin (600 mg daily for 22 days).
  • Measurement of total and fractional metabolic clearances of propranolol before and after rifampin treatment.

Main Results:

  • Rifampin increased total oral clearance of propranolol approximately fourfold in both EMs and PMs.
  • Impaired 4-hydroxypropranolol formation in PMs was confirmed.
  • 4-Hydroxylation induction by rifampin was fifteenfold greater in EMs compared to PMs, while glucuronidation induction was similar.

Conclusions:

  • Rifampin induces propranolol metabolism in both EMs and PMs, but to different extents.
  • The debrisoquin-defined cytochrome P450 or associated hydroxylases are induced more significantly in EMs.
  • These findings highlight the differential impact of rifampin on specific metabolic pathways based on genetic phenotype.

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