Selective effects of somatostatin analogs on human drug-metabolizing enzymes.
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.
Rasmussen
E
E
Department of Clinical Pharmacology, University Hospital, Uppsala, Sweden.
Eriksson
B
B
Oberg
K
K
Bondesson
U
U
Rane
A
A
D000328:Adult; D000368:Aged; D000701:Analgesics, Opioid / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D003061:Codeine / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D019389:Cytochrome P-450 CYP2D6 / Q000187:drug effects* / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D006727:Hormone Antagonists / Q000097:blood / Q000494:pharmacology* / Q000652:urine; D006801:Humans; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000187:drug effects* / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy; D013004:Somatostatin / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology* / Q000652:urine
D000701:Analgesics, Opioid; D006727:Hormone Antagonists; D013004:Somatostatin; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D003061:Codeine