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Relationship between cytochrome P-450 induction by rifampicin, hepatic volume and portal blood flow in man
Objective:
Induction of hepatic cytochrome P-450-dependent oxidative metabolism is related to an almost identical increase (30%) in both the liver weight and portal blood flow in animals. In humans by contrast, an increased liver blood flow (44%) but no significant increase in liver volume has been reported.
Design:
Therefore, we studied prospectively the relationship between P-450 induction by rifampicin, hepatic volume and portal blood flow in 10 healthy volunteers.
Methods:
After a pre-treatment phase (day 1 to 7) the 10 volunteers received 600 mg/day of rifampicin from day 7 to 12. The urinary 6-beta-hydroxycortisol output as a measure of oxidative metabolism (CYP3A4) and portal blood flow (pulsed Doppler ultrasound) were determined on days 1, 7, 11 and 13. Hepatic magnetic resonance volumetry was performed on days 1 and 13.
Results:
Urinary 6-beta-hydroxycortisol output increased in all volunteers (P = 0.0051) from a median of 2.15 micrograms/day/kg (1.8-3.3 micrograms/day/kg) on day 1 to 9.9 micrograms/day/kg (5.7-14 micrograms/day/kg) on day 13. In 9 of 10 volunteers induction by rifampicin was related to an increase (P = 0.0218) in liver volume from a median of 1570 cm3 (1390-1830 cm3) to a median of 1690 cm3 (1420-1860 cm3). The portal flow as assessed by colour Doppler ultrasound did not change significantly between day 1 (median 22 cm/s (15-35 cm/s)) and day 13 (median 19 cm/s (16-39 cm/s)).
Conclusion:
A fourfold increase of urinary 6-beta-hydroxycortisol output after induction of cytochrome P-450 by rifampicin is associated with a significant but less than 10% increase in human liver volume. No increase of portal perfusion as assessed by Doppler ultrasound could be detected in this study.
Insights
Rifampicin significantly increases liver volume by less than 10% in humans, alongside a fourfold rise in cytochrome P-450 metabolism. Portal blood flow did not show significant changes in this study.
Area of Science:
- Pharmacology
- Hepatology
- Human Physiology
Background:
- Hepatic cytochrome P-450-dependent oxidative metabolism induction in animals correlates with increased liver weight and portal blood flow.
- Human studies have reported increased liver blood flow but not significant liver volume changes upon P-450 induction.
Purpose of the Study:
- To investigate the relationship between P-450 induction by rifampicin, hepatic volume, and portal blood flow in healthy human volunteers.
Main Methods:
- Prospective study involving 10 healthy volunteers receiving rifampicin (600 mg/day) for 6 days.
- Measured urinary 6-beta-hydroxycortisol output (CYP3A4 activity) and portal blood flow (Doppler ultrasound) on specified days.
- Assessed hepatic magnetic resonance volumetry on days 1 and 13.
Main Results:
- Urinary 6-beta-hydroxycortisol output significantly increased (P = 0.0051), indicating P-450 induction.
- Liver volume increased by less than 10% in 9 out of 10 volunteers (P = 0.0218).
- Portal blood flow showed no significant change between day 1 and day 13.
Conclusions:
- Rifampicin-induced P-450 metabolism in humans is associated with a modest increase in liver volume, unlike findings in animal models.
- No significant alteration in portal perfusion was detected via Doppler ultrasound in this study.