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Effects of erythromycin on hepatic drug-metabolizing enzymes in humans
Abstract:
In rats, erythromycin has been shown to induce microsomal enzymes and to promote its own transformation into a metabolite which forms an inactive complex with reduced cytochrome P-450. To determine whether similar effects also occur in humans, we studied hepatic microsomal enzymes from six untreated patients and six patients treated with erythromycin propionate, 2 g per os daily for 7 days. In the treated patients, NADPH-cytochrome c reductase activity was increased; the total cytochrome P-450 concn was also increased but part of the total cytochrome P-450 was complexed by an erythromycin metabolite. The concn of uncomplexed (active) cytochrome P-450 was not significantly modified and the activity of hexobarbital hydroxylase remained unchanged. We also measured the clearance of antipyrine in six other patients; this clearance was not significantly decreased when measured again on the seventh day of the erythromycin propionate treatment. We conclude that the administration of erythromycin propionate induces microsomal enzymes and results in the formation of an inactive cytochrome P-450-metabolite complex in humans. However, the concn of uncomplexed (active) cytochrome P-450 and tests for in vitro and in vivo drug metabolism were not significantly modified.
Insights
Erythromycin propionate induces liver microsomal enzymes in humans, forming an inactive complex with cytochrome P-450. However, active enzyme levels and drug metabolism tests showed no significant changes.
Area of Science:
- Pharmacology
- Biochemistry
- Drug Metabolism
Background:
- Erythromycin is known to induce microsomal enzymes in rats.
- This induction involves self-metabolism and complex formation with cytochrome P-450.
- The effects of erythromycin on human hepatic microsomal enzymes are not fully understood.
Purpose of the Study:
- To investigate whether erythromycin propionate induces hepatic microsomal enzymes in humans.
- To determine if erythromycin propionate forms an inactive complex with cytochrome P-450 in humans.
- To assess the impact of erythromycin propionate on drug metabolism in humans.
Main Methods:
- Studied hepatic microsomal enzymes from untreated and erythromycin propionate-treated patients.
- Measured NADPH-cytochrome c reductase activity and total/uncomplexed cytochrome P-450 concentrations.
- Assessed hexobarbital hydroxylase activity in vitro and antipyrine clearance in vivo.
Main Results:
- Erythromycin propionate increased NADPH-cytochrome c reductase activity and total cytochrome P-450.
- A portion of total cytochrome P-450 formed an inactive complex with an erythromycin metabolite.
- Uncomplexed (active) cytochrome P-450 and hexobarbital hydroxylase activity remained unchanged.
- Antipyrine clearance did not significantly decrease after 7 days of treatment.
Conclusions:
- Erythromycin propionate induces microsomal enzymes in humans.
- An inactive cytochrome P-450-metabolite complex is formed.
- Despite enzyme induction and complex formation, active cytochrome P-450 and drug metabolism parameters were not significantly altered.