Sex Differences in Drug Disposition

Table 3

Sex differences in hepatic clearance by route of metabolism/elimination.

PHASE I ENZYMES
Metabolic route	Model substrates	Drugs metabolized by route	Sex-specific activity
CYP1A	Caffeine, nicotine paracetamol (acetaminophen)	Clomipramine, clozapine, olanzapine, paracetamol, tacrine, theophylline	M > F [65]
CYP2C9	Dapsone, (S)-mephenytoin	Ibuprofen, (S)-warfarin, tolbutamide, fluvastatin, glipizide, losartan, irbesartan, piroxicam, tolbutamide, phenytoin, fluvastatin, nelfinavir	M = F [66]
CYP2C19	(S)-Mephenytoin Diazepam	Lansoprazole, omeprazole, hexobarbital, mephobarbital, citalopram, celecoxib, irbesartan, imipramine, piroxicam, propranolol (in part)	M = F [67]
CYP2D6	Dextromethorphan, debrisoquine, sparteine	Codeine, encainide, flecainide, fluoxetine, hydrocodone, metoprolol, paroxetine, mexilitine, phenformin, propranolol, sertraline, timolol, haloperidol, clomipramine, desipramine, imipramine, propafenone, testosterone	M < F [68]
CYP2E1	Chlorzoxazone	—	M > F [69]
CYP3A	Midazolam, dapsone, cortisol, Lidocaine, nifedipine, erythromycin	Alprazolam, alfentanil, astemizole, atorvastatin, carbamazepine, cisapride, clarithromycin, cyclosporin, cyclophosphamide, diazepam,diltiazem, erythromycin, estradiol, fentanyl, indinavir, itraconazole, ketoconazole, lovastatin, quinidine, nimodipine, nisoldipine, quinidine, ritonavir, verapamil, tacrolimus, simvastatin, vincristine, vinblastine, tamoxifen, tirilazad, troglitazone	F > M [70]
PHASE II ENZYMES
Metabolic route	Model substrates	Drugs metabolized by route	Sex-specific activity
UDP-glucuronosyl-transferases	Caffeine	Clofibric acid, diflusinal, ibuprofen, mycophenolate, mofetil, paracetamol, zidovudine	M = F [68, 71]
Sulfotransferases	Caffeine	—	M > F [72]
N-Acetyl-transferases	Caffeine, dapsone	Catecholamine derivatives, mercaptopurine, isoniazid, hydralazine	M = F [73]
Methyl-transferases	Norepinehrine, epinephrine	Azathioprine, dopamine, levodopa, 6-mercaptopurine, thioguanine, tazathioprine	M > F [74]

Table modified from Soldin and Mattison [5].