Pathways

Alfentanil (also known as Alfenta or Rapifen) is analgesic that can bind to mu-type opioid receptor to activate associated G-protein in the sensory neurons of central nervous system (CNS), which will reduce the level of intracellular cAMP by inhibiting adenylate cyclase. The binding of alfentanil will eventually lead to reduced pain because of decreased nerve conduction and release of neurotransmitter. Hyperpolarization of neuron is caused by inactivation of calcium channels and activation of potassium channels via facilitated by G-protein.

Alfacalcidol is a vitamin D analogue used for the management of hypocalcemia, secondary hyperparathyroidism, and osteodystrophy in patients with chronic renal failure, as well as some types of rickets and osteomalacia. Vitamin D is a secosteroid generated in the skin when 7-dehydrocholesterol located there interacts with ultraviolet irradiation - like that commonly found in sunlight. Vitamin D3 produced in the skin undergoes hydroxylation in the liver using the enzyme vitamin D 25-hydroxylase to form 25-hydroxyvitamin D3 (calcidiol). The second hydroxylation happens in the kidneys using the enzyme 25-hydroxy vitamin D 1α-hydroxylase to give 1, 25-dihydroxyvitamin D3 (calcitriol). Calcitriol interacts with vitamin D receptors in the small intestine to enhance the efficiency of intestinal calcium and phosphorous absorption from about 10-15% to 30-40% and 60% increased to 80%, respectively. Furthermore, calcitriol binds with vitamin D receptors in osteoblasts to stimulate a receptor activator of nuclear factor kB ligand (or RANKL) which subsequently interacts with receptor activator of nuclear factor kB (NFkB) on immature preosteoclasts, causing them to become mature bone-resorbing osteoclasts. Such mature osteoclasts ultimately function in removing calcium and phosphorus from bone to maintain blood calcium and phosphorus levels. Moreover, calcitriol also stimulates calcium reabsorption from the glomerular filtrate in the kidneys. Calcitrol is also involved in parathyroid hormone regulation, by lowering parathyroid hormone secretion. In conditions like chronic renal failure, renal bone disease, hypoparathyroidism, and vitamin D dependent rickets, the kidneys' capacity for 1α-hydroxylation is impaired, leading to reduced production of endogenous 1,25-dihydroxyvitamin D and aberrated mineral metabolism. Alfacalcidol is rapidly converted in the liver to 1,25-dihydroxyvitamin D and works to restore the functions and activities of endogenous 1,25-dihydroxyvitamin D.

Alendronic acid is a drug that is not metabolized by the human body as determined by current research and biotransformer analysis. Alendronic acid passes through the liver and is then excreted from the body mainly through the kidney.

Alendronate is a second-generation bisphosphonate taken orally or IV and used for the treatment of conditions such as osteoporosis, Paget’s disease and hypercalcemia. Alendronate targets the mevalonate pathway in osteoclasts, the cells responsible for the break down of bone tissue. The mevalonate pathway starts off with acetyl-CoA forming acetoacetyl-CoA using acetyl-CoA acetyltransferase in the mitochondria. Acetyl-CoA and acetoacetyl-CoA then form HMG-CoA via HMG-CoA synthase. HMG-CoA is converted to mevalonate using the enzyme HMG-CoA reductase. Mevalonate kinase converts mevalonate into mevalonate-5P, which is then metabolized into mevalonate-5PP by phosphomevalonate kinase. Isopentenyl-PP is then formed from mevalonate-5PP via diphosphomevalonate decarboxylase. Farmesyl pyrophosphate converts isopentenyl-PP to geranyl-PP, then to farnesyl-PP. Farnesyl-PP goes on to form geranylgeranyl-PP through geranylgeranyl pyrophosphate synthase or squalene through squalene synthase. Squalene goes through a series of reactions to eventually form cholesterol. Alendronate binds to bone hydroxyapatite and when bone resorption occurs, alendronate enters the osteoclasts through endocytosis. Acidification of the endocytic vesicles releases the alendronate. Alendronate inhibits farnesyl pyrophosphate synthase, which reduces the production of downstream isoprenoid lipids like farnesyl-PP and geranylgeranyl-PP. these lipids are needed for a process called prenylation, to anchor cell surface proteins in the osteoclast membrane. Without prenylation, the osteoclast cannot attach to the bone, therefore they are unable to function and undergo apoptosis. This decreases bone resorption/ break down as the osteoclasts are no longer able to survive. Adverse effects like GI disturbances like peptic ulcers and oesophagitis, muscle and bone pain, stomach pain, osteonecrosis, diarrhea, constipation, nausea, flatulence, headache, dizziness and inflammatory responses may occur from taking alendronate.

Alendronate also known as alendronic acid is a bisphosphonate drug that is used to treat osteoporosis by preventing osteoclastic bone resorption. Alendronate is a second-generation bisphosphonate as it contains a nitrogen group that acts to inhibit farnesyl pyrophosphate synthase. It is administered orally, with low oral bioavailability it is recommended to not consume a meal an hour within the administration so as to not decrease the availability of the drug within the body. The drug binds to bone hydroxyapatite, when it undergoes resorption the alendronate is released and taken into the osteoclast by endocytosis. Within the cytosol of the osteoclast alendronate then acts by inhibiting farnesyl pyrophosphate synthase, which is essential for the prenylation of proteins needed for osteoclast survival. Some vitamin supplements may need to be taken in conjunction such as vitamin D , and avoidance of multivalent ions such as calcium, antacids and divalent ions as they will interrupt the absorption of the drug.

Alendronate (also known as alendronic acid) is a type of bisphosphonate medication with nitrogen that can inhibit FPP synthase, which can block the pathway that produce geranyl-PP and farnesyl pyrophosphate. Geranyl-PP and farnesyl pyrophosphate are the compounds that are required for small GTPase signalling proteins undergo post-translational farnesylation and geranylgeranylation. Therefore, lack the formation of geranyl-PP and farnesyl pyrophosphate can prevent osteoclast activity, which lead to prevention of reduced bone resorption and turnover.

Metabolites of Alectinib are predicted with biotransformer.