Chondroitin sulfate is referred as a symptomatic slow-acting drug for osteoarthritis because it improves articular function, and reduces joint swelling and effusion. In addition, chondroitin sulfate prevents joint space narrowing of the knee. We hypothesized that the anti-inflammatory effect of chondroitin sulfate is associated to a decrease in the activation of mitogen-activated protein kinases (MAPK) and of the transcription factors nuclear factor-κ B (NF-κ B) and activator protein-1 (AP-1). Cultured rabbit chondrocytes were stimulated with interleukin-1 β (IL-1 β ) in presence of chondroitin sulfate. Nuclear translocation of NF-κ B and AP-1, and nitrite concentrations (as an index for nitric oxide) was assessed 48 hr later. The effect of chondroitin sulfate on IL-1 β activation of extracellular signal-regulated kinase 1/2 (Erk1/2) and p38MAPK was documented by immunoblot. The effect of chondroitin sulfate on sodium nitroprusside-induced apoptosis was evaluated with the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labelling assay. Chondroitin sulfate reduced IL-1 β -induced NF-κ B nuclear translocation, but not AP-1 translocation, it decreased IL-1 β -induced phosphorylation of Erk1/2 and abrogated p38MAPK phosphorylation, but did not prevent IL-1 β -induced increase in nitrite. Finally, chondroitin sulfate decreased nitroprusside-induced apoptosis of the chondrocytes. These results suggest that some of the biological activities of chondroitin sulfate may be associated to the reduction in Erk1/2 and p38MAPK phosphorylation and nuclear transactivation of NF-κ B.

No abstract

In humans, oral bioavailability of nifedipine has been reported to be around 60%, although the organ(s) contributing to its first-pass metabolism have not been determined. The aim of this study was to determine in vivo, in anesthetized and conscious rabbits the role of the intestine, liver, and lungs in the first-pass metabolism of nifedipine. To assess the extraction of nifedipine by the intestine, liver, and lungs, nifedipine was administered before and after each organ, and serial blood samples were withdrawn from an artery. In conscious rabbits, the systemic clearance of nifedipine injected into a lateral vein of an ear was 14.6 +/- 1.6 ml/min per kg, a value that was slightly decreased by anesthesia. In anesthetized rabbits, compared to the clearance estimated when nifedipine was administered into the thoracic aorta, the administration of nifedipine into a jugular vein, into the portal vein, or into the portal vein, or into the duodenum did not increase the value of the systemic clearance. In conscious rabbits, the clearance of nifedipine estimated when the drug was administered into the duodenum, the peritoneum, the portal vein, or into the jugular vein was identical to the clearance calculated when the drug was injected into the thoracic aorta. In vitro, nifedipine was metabolized in liver and intestinal epithelial cells homogenates but not in lungs or kidneys. We concluded that in the rabbit, oral nifedipine is not subjected to a first-pass metabolism, even though the intestine and the liver may contribute to nifedipine systemic clearance.

No abstract

Frusemide is removed from the body by biotransformation and renal secretion, but since frusemide metabolism is not altered in patients with hepatic cirrhosis, the role of the liver may be questioned. The aim of the study was to investigate which organs contribute to the first‐pass metabolism and systemic clearance of frusemide. Groups of anaesthetized New Zealand rabbits were administered frusemide proximally (prox) and distally (dist) to different organs, and blood was sampled from the abdominal aorta. The area under frusemide plasma concentrations‐time curve (AUC0‐∞) was calculated and frusemide extraction by an organ was estimated from the ratio (AUCdist‐AUCprox)/AUCdist. The small intestine extracted 83% of the absorbed dose of frusemide but the first‐pass uptake by the liver and lungs was negligible. To assess the contribution of the intestine and the kidneys to the systemic clearance of frusemide, it was injected into the jugular vein and blood was sampled proximal and distal to each organ. The kidneys extracted 24% of frusemide circulating in the renal arteries; on the other hand, the ability of the intestine to extract frusemide from the systemic circulation could not be detected. The lungs did not metabolize frusemide in vitro; the rate of metabolism of frusemide in vitro by kidneys was similar to that estimated in the intestine, and both rates were faster (P<0.05) than that observed in the liver. It is concluded that in rabbits, presystemic metabolism of frusemide is carried out by the intestine, and that systemic clearance of frusemide is mainly performed by the kidneys, although other organs, such as the intestine and the liver, must contribute to it.