SELECTIVE EFFECTS OF SOMATOSTATIN ANALOGS ON HUMAN DRUG-METABOLIZING-ENZYMES

Pharmacologic or surgical manipulation with growth hormone secretion o r with the physiologic release of somatostatin and growth hormone-rele asing hormone affects some rat liver enzymes, especially the sex-diffe rentiated ones. We investigated the effects of two somatostatin analog s on several enzyme functions in six patients with carcinoid syndrome, using codeine as a probe drug. Codeine was given intravenously and it s N- and O-demethylation, as well as 6-glucuronidation catalyzed by CY P3A, CYP2D6, and uridine diphosphate-glucuronosyltransferase, respecti vely, were studied before and during treatment with somatostatins, Aft er 3 days of treatment with somatostatins the partial metabolic cleara nce of codeine by N-demethylation decreased by 21% to 64% in all patie nts (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 a ll patients, 35%; p < 0.05), In contrast, the partial clearance by 6-g lucuronidation and the total systemic clearance of codeine were unchan ged. Our results may be caused by the inhibition of growth hormone sec retion induced by the somatostatins, inasmuch as direct metabolic inte ractions with these peptide drugs are improbable. The decline in CYP3A 4 and CYP2D6 activity might have clinical implications when substrates of these enzymes with low therapeutic indices are combined with somat ostatin analogs. Because the formation of morphine from codeine was al tered, the analgesic effect of this drug may be reduced during concomi tant treatment with somatostatins.