Biomedical subjects

François A Leblond

Publications and source records attributed to François A Leblond.

3 recordsLinked to original sources

PubMed2006

Evidence that the mouse osteocalcin-related gene does not encode nephrocalcin.

BACKGROUND/AIMS: The osteocalcin-related gene (ORG) is a mouse-specific member of the osteocalcin gene cluster predicted to encode a gamma-carboxyglutamic acid-rich protein. ORG mRNA has been predicted to encode nephrocalcin and shown to be expressed in the kidney where it could serve as an important crystallization inhibitor. To determine whether ORG encodes mouse nephrocalcin, we investigated its in vivo and in vitro expression. METHODS: We expressed fluorescent fusion ORG proteins in kidney cell lines and generated transgenic mice expressing enhanced green fluorescent protein under the control of the ORG promoter. RESULTS: ORG mRNA was shown to be expressed in mouse kidneys and in a variety of other tissues. Fusion constructs transfected in opossum kidney cells demonstrated integrity of the open reading frame with the presence of a protein of the expected molecular weight. However, kidneys from transgenic mice carrying the enhanced green fluorescent protein gene under the control of the ORG promoter (5.8 kb fragment) demonstrated no expression of the transgene in kidneys or other tissues. CONCLUSION: We conclude that ORG, the third gene of the mouse osteocalcin gene cluster is silent and unlikely to play a major role in mouse renal physiology.

Animals↗

PubMed2005

A study of the effect of temperature on the pharmacokinetic profile of raltitrexed administered by intraperitoneal route in the rat.

BACKGROUND: Because heat can improve the activity of selected drugs when administered heated in the peritoneal cavity in the treatment of peritoneal carcinomatosis from colorectal origin, there is a great interest to evaluate new cytotoxic agents in this context. The purpose of this study is to assess the effect of heat on the pharmacokinetic profile of Raltitrexed administered intraperitoneally in rats. MATERIAL/METHODS: Rats #1 to #40 have been submitted to different doses of intraperitoneal Raltitrexed (2, 4, and 8 mg/m2) at different perfusion temperatures (37, 40 and 43 degrees C). After 25 minutes of perfusion, peritoneal fluid, portal and systemic blood were harvested and prepared for dosage of Raltitrexed. Rats #41 to #50 have been submitted to 8 mg/m2 of intraperitoneal Raltitrexed (37 and 43 degrees C) during 25 minutes. Then, a segment of small bowel and a section of parietal peritoneum were harvested and prepared for intracellular dosage of Raltitrexed. RESULTS: The dose of Raltitrexed administered is a determinant of its concentration in peritoneal perfusate, in portal vein blood and in systemic blood (p < 0.0002). We noticed that perfusate temperature had no significant effect on the concentration of drug in the portal vein blood (p = 0.29) and in the systemic blood (p = 0.25). However, temperature increased significantly (p < 0.04) the intracellular absorption of Raltitrexed. CONCLUSIONS: Because the effect of Raltitrexed is proportional to its intracellular concentration, it seems clear that Raltitrexed is of greatest interest when administered heated in the peritoneum because it can reach greater intracellular concentrations without a significant increase in systemic concentration, which is responsible of toxicity.

Animals↗

PubMed2003

Drug metabolism in chronic renal failure.

Pharmacokinetic studies conducted in patients with CRF demonstrate that the nonrenal clearance of multiple drugs is reduced. Although the mechanism by which this occurs is unclear, several studies have shown that CRF affects the metabolism of drugs by inhibiting key enzymatic systems in the liver, intestine and kidney. The down-regulation of selected isoforms of the hepatic cytochrome P450 (CYP450) has been reported secondary to a decrease in gene expression. This is associated with major reductions in metabolism of drugs mediated by CYP450. The main hypothesis to explain the decrease in liver CYP450 activity in CRF appears to be the accumulation of circulating factors which can modulate CYP450 activity. Liver phase II metabolic reactions are also reduced in CRF. On the other hand, intestinal drug disposition is affected in CRF. Increased bioavailability of several drugs has been reported in CRF, reflecting decrease in either intestinal first-pass metabolism or extrusion of drugs (mediated by P-glycoprotein). Indeed, intestinal CYP450 is also down-regulated secondary to reduced gene expression, whereas, decreased intestinal P-glycoprotein activity has been described. Finally, although the kidneys play a major role in the excretion of drugs, it has the capacity to metabolize endogenous and exogenous compounds. CRF will lead to a decrease in the ability of the kidney to metabolize drugs, but the repercussions on the systemic clearance of drugs is still poorly defined, except for selected xenobiotics. In conclusion, reduced drug metabolism should be taken into account when evaluating the pharmacokinetics of drugs in patients with CRF.

ATP Binding Cassette Transporter, Subfamily B↗