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Drug intraction of fenayl butazole and tolbutamide

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phenylbutazone tolbutamide drug interaction

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Drug Interaction: Phenylbutazone + Tolbutamide

Phenylbutazone (a pyrazolone NSAID, also written "fenayl butazole") is a potent interacting drug with tolbutamide (a first-generation sulfonylurea oral hypoglycemic). This is a clinically significant, well-documented interaction.

Mechanism of Interaction

There are two overlapping pharmacokinetic mechanisms:

1. Inhibition of Hepatic Metabolism (CYP2C9 inhibition)

Phenylbutazone inhibits the metabolism of tolbutamide (and other sulfonylurea drugs) in the liver. This prolongs the half-life of tolbutamide and raises its plasma concentration, intensifying and prolonging its blood glucose-lowering effect.
  • Katzung Table 4-6 explicitly lists phenylbutazone as an inhibitor of tolbutamide metabolism alongside phenytoin.
  • This is the same mechanism by which phenylbutazone also inhibits metabolism of S-warfarin (increased bleeding risk) and phenytoin (increased toxicity).

2. Displacement from Plasma Protein Binding

Phenylbutazone also displaces tolbutamide from plasma protein binding sites (mainly albumin). This transiently increases the free (unbound, pharmacologically active) fraction of tolbutamide in plasma.
  • While displacement alone is usually self-limiting, when combined with metabolic inhibition, the free drug cannot be cleared efficiently - leading to accumulation.

Clinical Consequence

EffectResult
Raised free tolbutamide levelsEnhanced hypoglycemic action
Prolonged tolbutamide half-lifeDuration of hypoglycemia extended
Additive with protein displacementGreater exposure to active drug
The net effect is an increased risk of severe, prolonged hypoglycemia.

Drugs in the Same Class with Similar Interaction

Oxyphenbutazone and azapropazone (same drug class as phenylbutazone) share this interaction with sulfonylureas by the same mechanism.

Management

From Rheumatology (Elsevier, 2022), the recommended approach is:
"Avoid this group of NSAIDs if possible; if not, monitor the blood glucose level closely."
Practical steps:
  • Avoid phenylbutazone in patients on tolbutamide or any sulfonylurea if possible.
  • If co-administration is unavoidable, reduce the tolbutamide dose empirically and monitor blood glucose frequently.
  • Watch for hypoglycemia symptoms: sweating, tremor, confusion, palpitations.
  • Consider switching to a different NSAID with less CYP2C9 inhibitory potential (e.g., sulindac, ibuprofen at low doses).

Sources

  • Katzung's Basic and Clinical Pharmacology, 16th Ed., Table 4-6 - Phenylbutazone listed as inhibitor of tolbutamide (and phenytoin) metabolism.
  • Rheumatology, 2-Vol Set (Elsevier, 2022), Table 61.2 - "Inhibition of the metabolism of sulfonylurea drugs, which prolongs the half-life and increases the risk for hypoglycemia."
  • A 1974 case letter in NEJM (Tannenbaum et al.) specifically described the phenylbutazone-tolbutamide drug interaction.
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