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liujiashen木蟲 (正式寫手)
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Pharmacokinetics Non-clinical pharmacokinetic studies were conducted mainly in Wistar rats and dogs. Toxicokinetic data were collected from repeated dose studies in mice (CD-1), rats, dogs and female rabbits. General organ distribution was studied in Wistar rats and pigmented rats; placental transfer and excretion into milk was studied in female Wistar rats. Plasma protein binding and metabolism were investigated in vitro in several species, including Cynomolgus monkeys and humans. Several in vitro studies were conducted to characterise the involvement, inhibition and induction of cytochrome Ps (CYPs), P-gp and Bcrp. Finally, cell permeability was studied in Caco-2 cells. Absorption after a single oral dose of rivaroxaban was rapid in both rats and dogs with maximal plasma concentration achieved in about 0.5 hours. The extent of absorption was somewhat lower in rats (67%) than in dogs (92%). After repeat dosing for 4 weeks, there was an increased absorption in rats, but not in mice or dogs. Higher exposure was observed in the female rats. Protein binding varied between species, highest being in rat (98.7%) and lowest in rabbit (76.6%). Mechanistic studies showed that serum albumin is the main binding protein. However, a mechanistic study with human serum albumin (HSA) and oleic acid showed a striking difference in protein binding depending on the oleic acid concentration. This difference in protein binding is large enough to cover almost the entire range observed in different species. Organ distribution after a single oral dose of rivaroxaban shows highest concentrations in the gastro- intestinal tract, liver and kidneys, lower concentrations in the brain. Rivaroxaban showed minor affinity to melanin-containing tissues, such as pigmented skin areas and eyes. After repeated oral administration to rats (14 consecutive daily administrations), radioactivity showed a moderate accumulation tendency. A slow elimination of rivaroxaban and its metabolites from bone after repeated dosing raised a suspicion of a potential connection with skeletal malformations observed in the reproductive toxicity studies. However, the detailed review of the data revealed that the absolute retention in bone is unlikely to prolong exposure and thus cause adverse effects on skeleton. Nevertheless, the embryotoxic observation (see section on Toxicology) remains and is addressed in the SPC. Volume of distribution was moderate, amounting to 0.3 L/kg for the rat and to 0.4 L/kg for the dog. Rivaroxaban was eliminated from rat and dog plasma with half-lives between 1 and 2 h. Rivaroxaban passes through the placental barrier but does not accumulate in the foetuses. In rats, the substance is excreted in milk. Rivaroxaban is subject to oxidative metabolism in liver. The in vivo biotransformation pathways of rivaroxaban in man are similar to those in animals and are reflected in the in vitro investigation with liver microsomes and cultured hepatocytes from different species. The main metabolic pathway, the oxidative degradation of the morpholinone moiety, was catalyzed by CYP3A4/3A5 and CYP2J2 and lead via cleavage of the ring and further oxidation to the formation of metabolite M1. Another pathway is the hydrolysis of the amide bond, generating metabolites M15 and M13. Besides unchanged rivaroxaban, metabolite M1 was identified as main metabolite in the excreta of animals and man. Qualitatively, the animal metabolism of rivaroxaban is similar to that of man and there are no unique human metabolites. There are quantitative differences but none of them represent a cause for concern. Elimination of rivaroxaban from plasma was rapid with no major circulating metabolites detected in plasma of rat, dog, and man. The main excretion routes in the investigated animal species and in man were renal and faecal/biliary. The rat differs from dogs and humans by a higher proportion of rivaroxaban and metabolites excreted in bile/faeces, and a lower proportion excreted in urine. |
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