Pharmacokinetics of the novel antiestrogenic agent toremifene in subjects with altered liver and kidney function.
OBJECTIVE
The pharmacokinetics of toremifene was investigated in an open study with four parallel groups of 10 subjects each. Subjects with impaired liver function (biopsy-proven liver disease), activated liver function (drug-induced), and impaired kidney function were compared with normal subjects.


METHODS
A single oral 120 mg dose of toremifene was administered after an overnight fast, and blood samples were collected over 28 days. Serum levels of toremifene and its metabolites were determined; appropriate pharmacokinetic parameters were calculated and statistically evaluated.


RESULTS
In normal subjects, the average peak level of 414 ng/ml toremifene was achieved at 3 hours after dosing, the terminal half-life was 6.2 days, apparent oral clearance was 5.1 L/hr, apparent volume of distribution was 958 L, and the fraction not bound to protein was 0.3%. The peak level (130 ng/ml) of the major metabolite, N-demethyltoremifene, appeared in serum with large variation in the time to peak level (median, 3 days) and a terminal half-life of 21.0 days. Low levels of deaminohydroxytoremifene were also measured, and two other metabolites could be quantified at some time points in some patients. The elimination rate of toremifene and the main metabolite was significantly increased in patients with activated liver function, resulting in decreased terminal half-lives (3.0 days and 4.5 days, respectively), and was decreased in patients with impaired liver function (10.9 days and 29.6 days, respectively). The subjects with impaired kidney function showed normal elimination kinetics.


CONCLUSIONS
Liver, but not kidney, function should be taken into account when toremifene is administered.
Anttila
M
M
Orion Corporation, Farmos Research, Turku, Finland.
Laakso
S
S
Nyländen
P
P
Sotaniemi
E A
EA
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D001189:Aryl Hydrocarbon Hydroxylases; D065637:Cytochrome P-450 CYP2A6; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects; D005260:Female; D006801:Humans; D007674:Kidney Diseases / Q000378:metabolism* / Q000503:physiopathology; D008107:Liver Diseases / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000187:drug effects; D017312:Toremifene / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology
D017312:Toremifene; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C104464:CYP3A protein, human; D065637:Cytochrome P-450 CYP2A6; D051544:Cytochrome P-450 CYP3A