Growth hormone replacement therapy induces codeine clearance.
BACKGROUND
The increasing clinical use of growth hormone (GH) has raised questions about other than growth-related metabolic effects of this treatment. GH regulates the expression of several hepatic drug metabolising enzymes in the rat, but it is not known whether GH treatment alters the expression of such liver enzymes in man. We have investigated the effects of GH on codeine clearance and two enzymes of the cytochrome P450 (CYP) family, CYP3A and CYP2D6, and UDP-glucuronosyl transferase (UDPGT). These enzymes have a superior importance in hepatic biotransformation of numerous drugs. In addition, CYP3A and UDPGT are catalysts of many reactions with endobiotics such as steroid hormones.


METHODS
We used codeine as a probe drug for assessment of the enzyme activities. Codeine was administered as a single-dose prior to, and after 3 months of GH substitution in GH-deficient patients. Total clearance, and clearance along each of the three primary metabolic pathways of codeine, was assessed.


RESULTS
Three months of GH substitution increased the total clearance of codeine (21%, P < 0.01) and clearance catalysed by UDPGT significantly (31%, P < 0.05). The treatment tended to increase the clearance via the CYP3A pathway (83%, P = 0.05).


CONCLUSIONS
The effects of GH replacement therapy on drug metabolism may have clinical implications when combined with drugs that are substrates of UDPGT and CYP3A. Effects on steroid hormone metabolism with endocrine consequences can not be ruled out.
Gil Berglund
E
E
The Medical Products Agency, Uppsala, Sweden.
Johannsson
G
G
Beck
O
O
Bengtsson
B-A
BA
Rane
A
A
D000328:Adult; D003061:Codeine / Q000493:pharmacokinetics* / Q000652:urine; D018592:Cross-Over Studies; D005260:Female; D013006:Growth Hormone / Q000172:deficiency* / Q000627:therapeutic use*; D006207:Half-Life; D006801:Humans; D007018:Hypopituitarism / Q000188:drug therapy / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects; D008875:Middle Aged; D009294:Narcotics / Q000493:pharmacokinetics* / Q000652:urine
D009294:Narcotics; D013006:Growth Hormone; D003061:Codeine