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Selective effects of somatostatin analogs on human drug-metabolizing enzymes
E Rasmussen1, B Eriksson, K Oberg
1Department of Clinical Pharmacology, University Hospital, Uppsala, Sweden.
Abstract:
Pharmacologic or surgical manipulation with growth hormone secretion or with the physiologic release of somatostatin and growth hormone-releasing hormone affects some rat liver enzymes, especially the sex-differentiated ones. We investigated the effects of two somatostatin analogs on several enzyme functions in six patients with carcinoid syndrome, using codeine as a probe drug. Codeine was given intravenously and its N- and O-demethylation, as well as 6-glucuronidation catalyzed by CYP3A, CYP2D6, and uridine diphosphate-glucuronosyltransferase, respectively, were studied before and during treatment with somatostatins. After 3 days of treatment with somatostatins the partial metabolic clearance of codeine by N-demethylation decreased by 21% to 64% in all patients (mean change, 44%; p < 0.05), and the clearance by O-demethylation was decreased by 20% to 69% in five of the patients (mean change in all patients, 35%; p < 0.05). In contrast, the partial clearance by 6-glucuronidation and the total systemic clearance of codeine were unchanged. Our results may be caused by the inhibition of growth hormone secretion induced by the somatostatins, inasmuch as direct metabolic interactions with these peptide drugs are improbable. The decline in CYP3A4 and CYP2D6 activity might have clinical implications when substrates of these enzymes with low therapeutic indices are combined with somatostatin analogs. Because the formation of morphine from codeine was altered, the analgesic effect of this drug may be reduced during concomitant treatment with somatostatins.
Insights
Somatostatin analogs reduced codeine metabolism by inhibiting CYP3A4 and CYP2D6 enzymes. This may decrease the analgesic effect of codeine when used with somatostatin analogs.
Area of Science:
- Pharmacology
- Drug Metabolism
- Endocrinology
Background:
- Growth hormone (GH) secretion and somatostatin/GH-releasing hormone (GHRH) influence liver enzymes, particularly sex-differentiated ones.
- Carcinoid syndrome patients often have altered hormonal balances and drug metabolism.
- Somatostatin analogs are used to manage carcinoid syndrome symptoms.
Purpose of the Study:
- To investigate the impact of somatostatin analogs on drug-metabolizing enzymes in patients with carcinoid syndrome.
- To assess the effect of somatostatins on the metabolism of codeine, a probe drug metabolized by CYP3A4, CYP2D6, and UGT enzymes.
Main Methods:
- Six patients with carcinoid syndrome received intravenous codeine before and during treatment with two somatostatin analogs.
- Codeine's N-demethylation (CYP3A4), O-demethylation (CYP2D6), and 6-glucuronidation (UGT) were quantified.
- Partial and total systemic clearance of codeine metabolites were analyzed.
Main Results:
- Somatostatin analog treatment significantly decreased codeine N-demethylation (mean 44% reduction) and O-demethylation (mean 35% reduction).
- These metabolic changes were observed in all or most patients, indicating a consistent effect of somatostatins.
- Codeine 6-glucuronidation and total systemic clearance remained unchanged, suggesting specific enzyme inhibition.
Conclusions:
- The observed reduction in codeine metabolism is likely due to somatostatin-induced inhibition of growth hormone secretion, rather than direct drug interaction.
- The decline in CYP3A4 and CYP2D6 activity has potential clinical implications for drugs with narrow therapeutic indices metabolized by these enzymes.
- Concomitant use of somatostatin analogs may alter the analgesic efficacy of codeine due to changes in morphine formation.