Summary. Background: Thienopyridines are metabolized to active metabolites that irreversibly inhibit the platelet P2Y 12 adenosine diphosphate receptor. The pharmacodynamic response to clopidogrel is more variable than the response to prasugrel, but the reasons for variation in response to clopidogrel are not well characterized. Objective: To determine the relationship between genetic variation in cytochrome P450 (CYP) isoenzymes and the pharmacokinetic/pharmacodynamic response to prasugrel and clopidogrel. Methods: Genotyping was performed for CYP1A2, CYP2B6, CYP2C19, CYP2C9, CYP3A4 and CYP3A5 on samples from healthy subjects participating in studies evaluating pharmacokinetic and pharmacodynamic responses to prasugrel (60 mg, n = 71) or clopidogrel (300 mg, n = 74). Results: In subjects receiving clopidogrel, the presence of the CYP2C19*2 loss of function variant was significantly associated with lower exposure to clopidogrel active metabolite, as measured by the area under the concentration curve (AUC 0-24 ; P = 0.004) and maximal plasma concentration (C max ; P = 0.020), lower inhibition of platelet aggregation at 4 h (P = 0.003) and poor-responder status (P = 0.030). Similarly, CYP2C9 loss of function variants were significantly associated with lower AUC 0-24 (P = 0.043), lower C max (P = 0.006), lower IPA (P = 0.046) and poor-responder status (P = 0.024). For prasugrel, there was no relationship observed between CYP2C19 or CYP2C9 loss of function genotypes and exposure to the active metabolite of prasugrel or pharmacodynamic response. Conclusions: The common loss of function polymorphisms of CYP2C19 and CYP2C9 are associated with decreased exposure to the active metabolite of clopidogrel but not prasugrel. Decreased exposure to its active metabolite is associated with a diminished pharmacodynamic response to clopidogrel.

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In this population, prasugrel (40-60 mg LD and 10-15 mg MD) achieves greater IPA and a lower proportion of pharmacodynamic non-responders compared with the approved clopidogrel dosing.

The Southern Ocean exerts a strong impact on marine biogeochemical cycles and global air‐sea CO2 fluxes. Over the coming century, large increases in surface ocean CO2 levels, combined with increased upper water column temperatures and stratification, are expected to diminish Southern Ocean CO2 uptake. These effects could be significantly modulated by concomitant CO2‐dependent changes in the region's biological carbon pump. Here we show that CO2 concentrations affect the physiology, growth and species composition of phytoplankton assemblages in the Ross Sea, Antarctica. Field results from in situ sampling and ship‐board incubation experiments demonstrate that inorganic carbon uptake, steady‐state productivity and diatom species composition are sensitive to CO2 concentrations ranging from 100 to 800 ppm. Elevated CO2 led to a measurable increase in phytoplankton productivity, promoting the growth of larger chain‐forming diatoms. Our results suggest that CO2 concentrations can influence biological carbon cycling in the Southern Ocean, thereby creating potential climate feedbacks.

Prasugrel and clopidogrel inhibit platelet aggregation through active metabolite formation. Prasugrel's active metabolite (R-138727) is formed primarily by cytochrome P450 (CYP) 3A and CYP2B6, with roles for CYP2C9 and CYP2C19. Clopidogrel's activation involves two sequential steps by CYP3A, CYP1A2, CYP2C9, CYP2C19, and/or CYP2B6. In a randomized crossover study, healthy subjects received a loading dose (LD) of prasugrel (60 mg) or clopidogrel (300 mg), followed by five daily maintenance doses (MDs) (15 and 75 mg, respectively) with or without the potent CYP3A inhibitor ketoconazole (400 mg/day). Subjects had a 2-week washout between periods. Ketoconazole decreased R-138727 and clopidogrel active metabolite Cmax (maximum plasma concentration) 34-61% after prasugrel and clopidogrel dosing. Ketoconazole did not affect R-138727 exposure or prasugrel's inhibition of platelet aggregation (IPA). Ketoconazole decreased clopidogrel's active metabolite AUC0-24 (area under the concentration-time curve to 24 h postdose) 22% (LD) to 29% (MD) and reduced IPA 28% (LD) to 33% (MD). We conclude that CYP3A4 and CYP3A5 inhibition by ketoconazole affects formation of clopidogrel's but not prasugrel's active metabolite. The decreased formation of clopidogrel's active metabolite is associated with reduced IPA.