Pharmacology
DrugBankDescription
Medroxyprogesterone acetate (MPA) is a progesterone derivative that is more resistant to metabolism for improved pharmacokinetic properties. MPA can be use to treat secondary amenorrhea, endometrial hyperplasia, abnormal uterine bleeding, osteoporosis, vasomotor symptoms in menopause, vulvar and vaginal atrophy, prevent pregnancy, manage pain in endometriosis, prevent pregnancy, and is also used in palliative care for endometrial and renal carcinoma. Medroxyprogesterone acetate was granted FDA approval on 18 June 1959.
Mechanism of Action
Medroxyprogesterone acetate (MPA) inhibits the production of gonadotropin, preventing follicular maturation and ovulation, which is responsible for it’s ability to prevent pregnancy. This action also thins the endometrium. MPA reduces nuclear estrogen receptors and DNA synthesis in epithelial cells of the endometrium. MPA can also induce p53 dependant apoptosis in certain cancer cell lines, and inhibit GABA-A receptors.
Pharmacodynamics
Medroxyprogesterone acetate (MPA) inhibits gonadotropin production, reduces nuclear estrogen receptors and DNA synthesis in epithelial cells of the endometrium, and induces p53 dependant apoptosis in cancer cell lines. MPA oral tablets have a half life of 40-60 hours and other formulations can have half lives that are considerably longer, so the duration of action is long. The therapeutic window is wide as patients may take doses ranging from 5mg orally daily to 1000mg as a depo injection weekly. Long term use of MPA is associated with a reduction in bone density and patients who taking MPA during adolescence may have lower peak bone mass than untreated patients, which can also increase the risk of osteoporosis and fractures in the future.
Metabolism
Medroxyprogesterone acetate undergoes beta hydroxylation to form the metabolites 6-beta (M-2), 2-beta (M-4), and 1-beta-hydroxymedroxyprogesterone acetate (M-3). M-2 and M-4 are further metabolized to 2-beta,6-beta-dihydroxymedroxyprogesterone (M-1). M-3 is further metabolized to 1,2-dehydromedroxyprogesterone acetate (M-5).
Absorption
Absorption of oral medroxyprogesterone acetate (MPA) varies considerably between formulations. A 1000mg oral dose reaches an average Cmax of 145-315nmol/L while a 500mg oral dose reaches an average Cmax of 33-178nmol/L with a Tmax of 1-3 hours and a lag time of half an hour. The AUC of a 500mg oral dose of MPA was 543.4-1981.1nmol\*L/h depending on formulation. Intramuscular MPA reaches a Cmax of 4.69±1.52nmol/L with a Tmax of 4.75±2.09 days and an AUC of 81.58±27.64days\*nmol/L. Subcutaneous MPA reaches a Cmax of 3.83±1.56nmol/L with a T±max of 6.52±2.07 days and an AUC of 72.26±38.73days\*nmol/L. However, the pharmacokinetics of MPA may also vary depending on injection site.
Toxicity
The oral LD50 in rats is >6400mg/kg and in mice is >16g/kg. The intraperitoneal LD50 in rats is >900mg/kg and in mice is >1500mg/kg. The subcutaneous LD50 in rats is >900mg/kg and in mice is>1500mg/kg. Patients experiencing and overdose or oral medroxyprogesterone acetate (MPA) may present with nausea, vomiting, breast tenderness, dizziness, abdominal pain, drowsiness, fatigue, and withdrawal bleeding. Treat patients by stopping MPA and beginning symptomatic treatment. Patients who have been given too much of a MPA depo injection should contact a healthcare professional, hospital emergency department, or local poison control immediately.
Indication
Medroxyprogesterone acetate (MPA) oral tablets are indicated to treat secondary amenorrhea, reduce the incidence of endometrial hyperplasia in postmenopausal women, and to treat abnormal uterine bleeding due to hormonal imbalance, not organic pathology. Oral tablets containing MPA and conjugated estrogens are indicated to prevent postmenopausal osteoporosis and to treat moderate to severe menopausal symptoms such as vasomotor symptoms, vulvar atrophy, and vaginal atrophy. Subcutaneous MPA is indicated to prevent pregnancy and manage pain associated with endometriosis. Intramuscular MPA is indicated to prevent pregnancy, and at higher concentrations for palliative treatment of endometrial or renal carcinoma.
Half-life
Oral medroxyprogesterone acetate (MPA) has an absorption half life of 15-30min and a biological half life of 40-60 hours. Intramuscular MPA has an absorption half life of 0.86±0.30 days and an elimination half life of 24.03±21.74 days. Subcutaneous MPA has an absorption half life of 1.05±0.56 days and an elimination half life of 30.90±15.11 days.
Protein Binding
Medroxyprogesterone acetate is 86% protein bound in serum, mainly to albumin. No binding occurs with sex hormone binding globulin.
Elimination
The majority of medroxyprogesterone acetate (MPA) is eliminated in the urine as glucuronide conjugates and a minority of sulphate conjugates. Glucuronide conjugates are also detected in the feces. Determining the exact ratio of metabolites and parent compound eliminated in the urine and feces is difficult as the metabolite profile in the urine is not significantly different and radio labelling studies are not readily available.
Volume of Distribution
The volume of distribution of medroxyprogesterone acetate is 20±3L.
Clearance
The mean clearance of medroxyprogesterone acetate (MPA) is 1668±146L/day or 21.9±4.3L/kg/day. Due to the high inter patient variability in MPA pharmacokinetics, clearance has been reported to be 1600-4000L/day.
Effect Profile
CuratedStrong euphoria with moderate itching/nausea, mild sedation