Pharmacodynamics<unk>  is a peripherally selective dopamine D2 and D3 receptor antagonist. It has no clinically significant interaction with the D1 receptor, unlike metoclopramide. The medication provides relief from nausea by blocking D2 receptors. It blocks dopamine receptors in the anterior pituitary gland increasing release of prolactin which in turn increases lactation.<unk>  may be more useful in some patients and cause harm in others by way of the genetics of the person, such as polymorphisms in the drug transporter gene ABCB1 (which encodes P-glycoprotein), the voltage-gated potassium channel KCNH2 gene (hERG/Kv11.1), and the α1D-adrenergic receptor ADRA1D gene. Effects on prolactin levels A single 20 mg oral dose of<unk>  has been found to increase mean serum prolactin levels (measured 90 minutes post-administration) in non-lactating women from 8.1 ng/mL to 110.9 ng/mL (a 13.7-fold increase). This was similar to the increase in prolactin levels produced by a single 20 mg oral dose of metoclopramide (7.4 ng/mL to 124.1 ng/mL; 16.7-fold increase). After two weeks of repeated administration (30 mg/day in both cases), the increase in prolactin levels produced by<unk>  was reduced (53.2 ng/mL; 6.6-fold above baseline), but the increase in prolactin levels produced by metoclopramide, conversely, was heightened (179.6 ng/mL; 24.3-fold above baseline). This indicates that acute and continuous administration of both<unk>  and metoclopramide is effective in increasing prolactin levels, but that there are different effects on the secretion of prolactin with repeated use. The mechanism of the difference is unknown. The increase in prolactin levels observed with the two drugs was much greater in women than in men. This appears to be due to the higher estrogen levels in women, as estrogen stimulates prolactin secretion from the pituitary gland. For comparison, normal prolactin levels in women are less than 20 ng/mL, prolactin levels peak at 100 to 300 ng/mL at parturition in pregnant women, and in lactating women, prolactin levels have been found to be 90 ng/mL at 10 days postpartum and 44 ng/mL at 180 days postpartum. Pharmacokinetics Absorption The absolute bioavailability of<unk>  is low (13–17% or approximately 15%). This is due to extensive first-pass metabolism in the intestines and liver. Conversely, its bioavailability is high via intramuscular injection (90%). The onset of action of<unk>  taken orally is about 30 to 60 minutes. Peak levels of<unk>  following an oral dose occur after about 60 minutes.<unk>  exposure increases proportionally with doses in the 10 to 20 mg dose range. There is a 2- to 3-fold accumulation in levels of<unk>  with frequent repeated oral administration of<unk>  (four times per day (every 5 hours) for 4 days). The oral bioavailability of<unk>  is somewhat increased and time to peak slightly increased when it is taken with food and bioavailability is decreased by prior concomitant administration of cimetidine and sodium bicarbonate. Distribution The plasma protein binding of<unk>  is 91 to 93%. The tissue distribution of<unk>  based on animal studies is wide, but concentrations are low in the brain. The drug is a substrate for the P-glycoprotein (ABCB1) transporter, and animal studies suggest that this is the reason for the low central nervous system penetration of<unk> . Small amounts of<unk>  cross the placenta in animals. Metabolism<unk>  is extensively metabolized in the liver and intestines with oral administration. This occurs via hydroxylation and N-dealkylation.<unk>  is almost exclusively metabolized by CYP3A4/5, though minor contributions by CYP1A2, CYP2D6, and CYP2C8 have been reported. CYP3A4 is the major enzyme involved in the N-dealkylation of<unk> , while CYP3A4, CYP1A2, and CYP2E1 are involved in its aromatic hydroxylation. All of the metabolites of<unk>  are inactive as D2 receptor ligands. Overall and peak levels of<unk>  are increased by about 2.9- and 1.5-fold in moderate hepatic impairment, respectively. Elimination<unk>  is eliminated 31% in urine and 66% in feces. The proportion of<unk>  excreted unchanged is small (10% in feces and 1% in urine). The elimination half-life of<unk>  is about 7 to 9 hours in healthy individuals. However, the elimination half-life of<unk>  can be prolonged to 20 hours in people with several renal dysfunction.
Domperidone
Primidone
Chlortalidone
Thioridazine
Cinolazepam
Fluparoxan
Mepiprazole
Ziprasidone