Use of midazolam as a human cytochrome P450 3A probe: II. Characterization of inter- and intraindividual hepatic CYP3A variability after liver transplantation.
Immunosuppression therapy with cyclosporine is often hampered by significant interindividual variability in the metabolic clearance of the drug. It has been suggested that much of the variability in cyclosporine clearance is due to differences in the cytochrome P450 3A4 (CYP3A4) content in the liver and intestinal mucosa. A study was conducted in liver transplant recipients to characterize hepatic CYP3A variability during the first 10 days after surgery. The formation of 1'-hydroxymidazolam (1'-OH MDZ) was followed in the plasma after i.v. midazolam (MDZ) administration to 21 multiple-organ donors and to recipients of 10 of the 21 donor livers. Liver biopsy tissue was obtained from donors and recipients after the in vivo pharmacokinetic test. For liver donors, the plasma 1'-OH MDZ/MDZ concentration ratio 30 min after the i.v. MDZ dose was well correlated with the hepatic CYP3A4 content (r = .87, P < .001). Much of the variability in the two parameters was attributed to the administration of enzyme-inducing drugs before organ procurement. The mean hepatic CYP3A4 content and plasma 1'-OH MDZ/MDZ concentration ratio in six inducer-treated donors was 4.7-fold and 2.3-fold higher than the respective mean value for all other donors. The hepatic CYP3A4 content and plasma 1'-OH MDZ/MDZ ratio for liver recipients, studied on postoperative day 10, was negatively correlated with the respective parameter measured in donors on day 0 (r = -0.60 for CYP3A4 and r = -0.79 for 1'-OH MDZ/MDZ; P < .05 and P < .01).(ABSTRACT TRUNCATED AT 250 WORDS)
Thummel
K E
KE
Department of Pharmaceutics, University of Washington, Seattle.
Shen
D D
DD
Podoll
T D
TD
Kunze
K L
KL
Trager
W F
WF
Bacchi
C E
CE
Marsh
C L
CL
McVicar
J P
JP
Barr
D M
DM
Perkins
J D
JD
D000293:Adolescent; D000328:Adult; D002648:Child; D019392:Cytochrome P-450 CYP2E1; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis*; D005260:Female; D006801:Humans; D008099:Liver / Q000201:enzymology*; D016031:Liver Transplantation; D008297:Male; D008874:Midazolam / Q000031:analogs & derivatives / Q000378:metabolism*; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000032:analysis*; D010672:Phenytoin / Q000494:pharmacology; D014019:Tissue Donors
D010672:Phenytoin; D003577:Cytochrome P-450 Enzyme System; C040081:1-hydroxymethylmidazolam; D006899:Mixed Function Oxygenases; D019392:Cytochrome P-450 CYP2E1; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D008874:Midazolam