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Source: Oxford English Dictionary online
Original passage:
Prospectively, there are always instances where in vivo human outcomes could not be fully appreciated from in vitro data. Retrospectively, however, in vitro systems are valuable tools to understand clinical DDIs. Cerivastatin, a potent HMGCoA reductase inhibitor, was thought to be at low risk of metabolism inhibition because the compound was metabolized by both CYP3A4 and CYP2C8; and the lack of clinically relevant interactions with commonly used drugs appeared to support this hypothesis. However, a significant interaction with gemfibrozil, and concerns over severe rhabdomyolysis associated with this type of interaction, led to its eventual withdrawl from the market. Subsequent investigative studies indicated that gemfibrozil-Oglucuronide, a major metabolite of gemfibrozil, is an inhibitor of cerivastatin hepatic uptake transport via the organic anion transporter protein, as well as a mechanism-based inactivator of CYP2C8 . Therefore, the impact of gemfibrozil on cerivastatin pharmacokinetics is likely to have been caused by a combination of hepatic uptake and CYP2C8 inhibition.
Source: Fowler, S., and Zhang, H. (2008) AAPS J. 10, 410-424.
Satisfactory summary:
In vitro drug-drug interaction studies are important tools to anticipate reactions in humans but they don’t always predict outcomes. Cerivastatin was considered to be at low risk for CYP inhibition but ultimately it interacted with gemfibrozil, causing the drug to be withdrawn from the market. Further investigation showed that a metabolite of gemfibrozil adversely affected cerivastation pharmacokinetics. (Fowler, Zhang, 2008).
Reference list
Fowler, S., and Zhang, H. (2008) AAPS J. 10, 410-424.
Plagiarized summary:
There are always instances where in vivo human outcomes could not be fully appreciated from in vitro data. Cerivastatin, a potent HMGCoA reductase inhibitor, was thought to be at low risk of metabolism inhibition because the compound was metabolized by both CYP3A4 and CYP2C8. However, a significant interaction with gemfibrozil, and concerns over severe rhabdomyolysis associated with this type of interaction led to its eventual withdrawal. Subsequent investigative studies indicated that gemfibrozil-Oglucuronide, a major metabolite of gemfibrozil, is an inhibitor of cerivastatin hepatic uptake transport as well as a mechanism-based inactivator of CYP2C8. The impact of gemfibrozil on cerivastatin pharmacokinetics is therefore likely to have been caused by a combination of hepatic uptake and CYP2C8 inhibition. Despite this example, in vitro systems remain valuable tools used to understand clinical drug-drug interactions. (Fowler, Zhang, 2008)
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