Prasugrel pharmacokinetics and pharmacodynamics in subjects with moderate renal impairment and end-stage renal disease.

OBJECTIVE: The pharmacokinetic (PK) and pharmacodynamic (PD) responses to prasugrel were compared in three studies of healthy subjects vs. those with moderate or end-stage renal impairment. METHODS: Two of the three protocols were parallel-design, open-label, single dose (60-mg prasugrel) studies in subjects with end-stage renal disease (ESRD; n = 12) or moderate renal impairment (n = 10) and matched healthy subjects with normal renal function (n = 10). The third protocol was an open-label, single-dose escalation (5, 10, 30 and 60 mg prasugrel) study in subjects with ESRD (n = 16) and matched healthy subjects with normal renal function (n = 16). Plasma concentrations of prasugrel's active metabolite were determined and pharmacokinetic parameter estimates were derived. Maximum platelet aggregation (MPA) was measured by light transmission aggregometry using 20 mum adenosine diphosphate as agonist. RESULTS: Across all studies, prasugrel's C(max) and AUC(0-t) were 51% and 42% lower in subjects with ESRD than in healthy subjects. AUC(0-t) did not differ between healthy subjects and subjects with moderate renal impairment. The magnitude of change and time-course profiles of MPA was similar for healthy subjects compared with subjects with moderate renal impairment and those with ESRD. Prasugrel was well-tolerated in all subjects. CONCLUSION: There was no difference in pharmacokinetics or PD responses between subjects with moderate renal impairment and healthy subjects. Despite significantly lower exposure to prasugrel's active metabolite in subjects with ESRD, MPA did not differ between healthy subjects and those with ESRD.

Luminal nutrients exacerbate intestinal hypoxia in the hypoperfused jejunum.

BACKGROUND: Provision of enteral nutrients shortly after traumatic injury has become the preferred method of nutrition support provided to patients. However, traumatic shock results in splanchnic hypoperfusion, which may cause persistent intestinal hypoxia. This study tested the hypothesis that delivery of enteral nutrients to the hypoperfused jejunum increases oxidative demand beyond that available, thereby exacerbating intestinal hypoxia. METHODS: Wistar-Furth rats (186+/-4 g; n = 24) were randomized to receive intestinal hypoxia (superior mesenteric artery occlusion) or serve as normoxic controls (sham laparotomy). Within the jejunum of each rat, 4 6-cm loops were randomized to receive luminal perfusions with 1 of 4 substrates: mannitol (an osmotic control); glucose (undergoes active transport via the sodium-glucose co-transporter [SGLT-1] and is metabolized); 3-o-methylglucose (3-o-mg; uses SGLT-1 but is not metabolized); or fructose (does not use SGLT-1 but is metabolized). After in situ perfusions, jejunal tissue was removed for analysis of nutrient transport and barrier function in modified Ussing chambers. Tissue homogenate was used to determine concentration of ATP, lactate, pyruvate, and protein. Also, jejunal tissue was stained with hematoxylin and eosin for qualitative analysis of ischemia and necrosis. RESULTS: Transmural resistance was lower (p < .001) in the hypoxia groups, irrespective of substrate, indicating increased mucosal permeability. When compared with the normoxic controls, glucose transport was impaired (p < .001) in the hypoxic groups; however, glutamine transport was unaffected. The degree of intestinal hypoxia, assessed by jejunal lactate concentration, was higher (p < .001) in the glucose and fructose groups, than the control mannitol and 3-o-mg groups. CONCLUSIONS: The observation that 3-o-mg did not differ from the mannitol control indicates that SGLT-1 activation alone does not exacerbate hypoxia. Rather, these results indicate that provision of metabolizable nutrients to the hypoperfused intestine exacerbate hypoxia and potentially lead to intestinal ischemia. Although early enteral nutrition is an important intervention after trauma, care must be taken to ensure intestinal perfusion is adequate to allow for nutrient metabolism and prevent further compromise.

2001 Harry M. Vars Research Award. Enteral nutrients alter enterocyte function within an in vitro model similar to an acute in vivo rat model during hypoxia.

BACKGROUND: Early enteral nutrition in patients following traumatic injury is an important intervention. However, after shock-resuscitation, intestinal hypoperfusion persists despite adequate systemic resuscitation. Our previous in vivo rat studies indicate that hypoperfusion impairs mucosal function in the small intestine. Therefore, the current study sought to improve previous in vitro models by the following means: (1) We used Caco-2 monolayers stably transfected with the brush-border sodium-glucose co-transporter (SGLT-1); and (2) we created an environment that mimicked the physiologic enterocyte environment. We hypothesized that hypoxic alterations of epithelial function in an in vitro model are comparable to those of an in vivo rat model. METHODS: After 21 days, monolayers were randomized to receive 24 hours of incubation in a normoxic or hypoxic environment. Cells were further randomized to receive 1 of 4 nutrient treatments: mannitol (an osmotic control), glucose (uses SGLT-1 and is metabolized), 3-O-methylglucose (3-O-mg; uses SGLT-1 and is not metabolized), or fructose (does not use SGLT-1 but can be metabolized). RESULTS: Transepithelial resistance (p = .007) and short-circuit current (p = .05) were lower in hypoxic groups. When compared with normoxic groups, hypoxic groups had significantly impaired glucose (p < .001) but not glutamine transport, irrespective of nutrient treatment. Additionally, adenosine triphosphate/adenosine diphosphate ratio was reduced (p = .01) and lactate concentration was increased (p < .001) during hypoxia. CONCLUSIONS: In summary, results from this in vitro study using Caco-2BBe cells stably transfected with SGLT-1 correspond to results obtained in the in vivo rat model. Therefore, this is an appropriate in vitro model in which to study cellular alterations caused by the hypoxic small intestine, with the goal of ensuring safe early enteral nutrition following traumatic injury.

Hypoxia differentially regulates nutrient transport in rat jejunum regardless of luminal nutrient present.

Aggressive enteral nutrition and poor intestinal perfusion are hypothesized to play an important pathogenic role in nonocclusive small bowel necrosis. This study tests the hypothesis that glucose and glutamine transport are differentially regulated during hypoxia regardless of the luminal nutrient present. Sprague-Dawley rats (247 +/- 3 g; n = 16) were randomized to receive 1 h of intestinal hypoxia or serve as normoxic controls. During this hour, jejunal loops were randomized to receive in situ perfusions of mannitol, glucose, or glutamine. When compared with normoxic groups, glucose but not glutamine transport was impaired (P < 0.001) during hypoxia. Messenger RNA abundance of the sodium glucose cotransporter sodium-dependent glucose cotransporter-1 (SGLT-1) and neutral basic amino acid transporter B(o) did not differ with hypoxia or nutrient perfused. Jejunal brush-border SGLT-1 abundance was decreased (P = 0.039) with hypoxia; however, total cellular SGLT-1 protein abundance did not differ among treatment groups. These data indicate that SGLT-1 activity is regulated during hypoxia at the posttranslational level. Additional information regarding the mechanisms regulating nutrient transport in the hypoperfused intestine is critical for optimizing the composition of enteral nutrient formulas.