Progesterone

Absorption

A. Absorption
After oral administration of progesterone as a soft-gelatin capsule formulation, maximum serum concentrations were attained within 3 hours. The absolute bioavailability of progesterone is not known. Table 1 summarizes the mean pharmacokinetic parameters in postmenopausal women after five oral daily doses of progesterone capsules 100 mg as a soft-gelatin capsule formulation.
TABLE 1. Pharmacokinetic Parameters of
Progesterone Capsules
Parameter
Progesterone Capsules
Daily Dose
100 mg
200 mg
300 mg
C
max(ng/mL)
17.3 ± 21.9
a
38.1 ± 37.8
60.6 ± 72.5
T
max(hr)
1.5 ± 0.8
2.3 ± 1.4
1.7 ± 0.6
AUC
(0-10)(ng × hr/mL)
43.3 ± 30.8
101.2 ± 66
175.7 ± 170.3
aMean ± S.D.
Serum progesterone concentrations appeared linear and dose proportional following multiple dose administration of progesterone capsules 100 mg over the dose range 100 mg per day to 300 mg per day in postmenopausal women. Although doses greater than 300 mg per day were not studied in females, serum concentrations from a study in male volunteers appeared linear and dose proportional between 100 mg per day and 400 mg per day. The pharmacokinetic parameters in male volunteers were generally consistent with those seen in postmenopausal women.
B. Distribution
Progesterone is approximately 96 percent to 99 percent bound to serum proteins, primarily to serum albumin (50 to 54 percent) and transcortin (43 to 48 percent).
C. Metabolism
Progesterone is metabolized primarily by the liver largely to pregnanediols and pregnanolones. Pregnanediols and pregnanolones are conjugated in the liver to glucuronide and sulfate metabolites. Progesterone metabolites which are excreted in the bile may be deconjugated and may be further metabolized in the intestine via reduction, dehydroxylation and epimerization.
D. Excretion
The glucuronide and sulfate conjugates of pregnanediol and pregnanolone are excreted in the bile and urine. Progesterone metabolites are eliminated mainly by the kidneys. Progesterone metabolites which are excreted in the bile may undergo enterohepatic recycling or may be excreted in the feces.
E. Special Populations
The pharmacokinetics of progesterone capsules have not been assessed in low body weight or obese patients.
Hepatic Insufficiency:
The effect of hepatic impairment on the pharmacokinetics of progesterone capsules has not been studied.
Renal Insufficiency:
The effect of renal impairment on the pharmacokinetics of progesterone capsules has not been studied.
F. Food–Drug Interaction
Concomitant food ingestion increased the bioavailability of progesterone capsules relative to a fasting state when administered to postmenopausal women at a dose of 200 mg.
G. Drug Interactions
The metabolism of progesterone by human liver microsomes was inhibited by ketoconazole (IC
50<0.1 μM). Ketoconazole is a known inhibitor of cytochrome P450 3A4, hence these data suggest that ketoconazole or other known inhibitors of this enzyme may increase the bioavailability of progesterone. The clinical relevance of the
in vitrofindings is unknown.
Co-administration of conjugated estrogens and progesterone capsules to 29 postmenopausal women over a 12-day period resulted in an increase in total estrone concentrations (C
max3.68 ng/mL to 4.93 ng/mL) and total equilin concentrations (C
max2.27 ng/mL to 3.22 ng/mL) and a decrease in circulating 17β estradiol concentrations (C
max0.037 ng/mL to 0.030 ng/mL). The half-life of the conjugated estrogens was similar with co-administration of progesterone capsules. Table 2 summarizes the pharmacokinetic parameters.
TABLE 2. Mean (± S.D.) Pharmacokinetic Parameters for Estradiol, Estrone and Equilin Following Co-administration of Conjugated Estrogens 0.625 mg and
Progesterone Capsules 200 mg for 12
Days to Postmenopausal Women
Conjugated
Estrogens
Conjugated Estrogens plus Progesterone
Capsules
Drug
C
max
(ng/mL)
T
max
(hr)
AUC
(0-24h)
(ng × h/mL)
C
max
(ng/mL)
T
max
(hr)
AUC
(0-24h)
(ng × h/mL)
Estradiol
0.037
± 0.048
12.7 …