Parathyroid hormone is an analog of human parathyroid hormone (PTH) used to treat hypocalcemia caused by hyperparathyroidism. Parathyroid hormone (PTH) is a single-chain polypeptide composed of 84 amino acids. Available as Protect, it is an identical form of human recombinant hormone which produced as a fusion protein undergoing post-translational processing involving the cleavage of the OmpA leader sequence, leaving the mature protein as a single-chain 84 amino-acids polypeptide (9.4 kDa).
Protect is used in the treatment of osteoporosis in postmenopausal women at high risk of osteoporotic fractures and is marketed in Europe by Nycomed. Press is a registered trademark owned by NPS Pharmaceuticals, Inc. The name Press and the New Drug Application is pending approval by the U.S. Food and Drug Administration (FDA).
Pharmacodynamics
- Parathyroid hormone is responsible for the fine regulation of serum calcium concentration on a minute-to-minute basis. This is achieved by the acute effects of the hormone on calcium resorption in bone and calcium reabsorption in the kidney. The phosphate mobilized from bone is excreted into the urine using the hormone’s influence on renal phosphate handling. Parathyroid hormone also stimulates calcium absorption in the intestine, this being mediated indirectly by 1,25-dihydroxy vitamin D. Thus, a hypocalcemic stimulus of parathyroid hormone secretion results in an increased influx of calcium from three sources (bone, kidney, and intestine), resulting in a normalization of the serum calcium concentration without change in the serum phosphate concentration.
Mechanism of action
- The biological actions of rhPTH are mediated through binding to at least two distinct high-affinity cell-surface receptors specific for the N-terminal and C-terminal regions of the molecule, both of which are required for normal bone metabolism. The N-terminal portion of the molecule is primarily responsible for the bone-building effects of parathyroid hormone. The C-terminal portion of the molecule has antiresorptive activity and is necessary for normal regulation of N-terminal fragment activity.
- Absorption
- The absolute bioavailability after subcutaneous administration in the abdomen is 55% for doses of 100 micrograms.
- Volume of distribution
- The volume of distribution at steady-state following intravenous administration is approximately 5.4 liters with an interpatient variability of about 40%.
- Protein binding
- Not Available
- Metabolism
- PTH is primarily metabolized in the liver with lesser contributions by the kidney. Amino-terminal fragments are metabolized in the liver. At the same time, carboxyl-terminal groups travel to the kidney for metabolism where they are also thought to have a role in the regulation of PTH. Only about 30% of circulating hormone is present in the unfragmented form.
- Route of elimination
- Carboxy-terminal fragments are filtered by the kidney and subsequently broken down into even smaller pieces during tubular reuptake.
- Half-life
- 1.5 hours.
- Clearance
- Not Available
Function
Parathyroid hormone is secreted from four parathyroid glands, which are small in the neck, and located behind the thyroid gland. Parathyroid hormone regulates calcium levels in the blood, largely by increasing the levels when they are too low. It does this through its actions on the kidneys, bones, and intestine:
- Bones – parathyroid hormone stimulates the release of calcium from large calcium stores in the bones into the bloodstream. This increases bone destruction and decreases the formation of new bone.
- Kidneys – parathyroid hormone reduces loss of calcium in the urine. Parathyroid hormone also stimulates the production of active vitamin D in the kidneys.
- Intestine–parathyroid hormone indirectly increases calcium absorption from food in the intestine, via its effects on vitamin D metabolism.
