CLOFIBRATE
Drugs in Pregnancy and Lactation.
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Name: CLOFIBRATE
Class: Antilipemic Agent
Risk Factor: CM
Fetal Risk Summary
No reports linking the use of clofibrate with congenital defects have been located. Animal reproduction studies have not been conducted with clofibrate (1).
There is pharmacologic evidence that clofibrate crosses the rat placenta and reaches measurable levels, but data in humans are lacking (2). The low molecular weight (about 243), however, indicates that the drug probably crosses the human placenta to the fetus. The drug is metabolized by glucuronide conjugation. Because this system is immature in the newborn, accumulation may occur. Consequently, the use of clofibrate near term is not recommended.
Breast Feeding Summary
No reports describing the use of clofibrate during human lactation have been located. Animal studies suggest that the drug is excreted into milk (2). The low molecular weight (about 243), also suggests that the drug is excreted into human milk. Moreover, the manufacturer states that an active metabolite has been measured in breast milk (1). Because of the potential for severe adverse effects in a nursing infant, the use of clofibrate should be considered contraindicated during breast feeding (1).
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References
- Product information. Atromid-S. Wyeth-Ayerst Pharmaceuticals, 2000.
- Chabra S, Kurup CKR. Maternal transport of chlorophenoxyisobutyrate at the foetal and neonatal stages of development. Biochem Pharmacol 1978;27:2063–5.
Q&A about Clofibrate
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Chlordiazepoxide undergoes oxidative metabolism in the liver, producing several active compounds including demoxepam, desmethylchlordiazepoxide, desmethyldiazepam, and oxazepam. Smoking enhances the hepatic metabolism of some benzodiazepines. Smokers may require increased doses to achieve the desired sedative effect. Chlordiazepoxide has a long half-life (5—30 hours) compared with other benzodiazepines, and the half-lives of its metabolites range from 14—100 hours. The risk of accumulation is high during periods of repeated dosing. Unchanged drug and its active metabolites are excreted in the urine, but the elimination is slower than that of other benzodiazepines because the metabolites can still be present in the blood for several weeks after the initial dosing interval.
Clofibrate is absorbed readily and completely from the GI tract and is rapidly hydrolyzed by serum esterases to the active metabolite clofibric acid. Clofibric acid peak plasma concentrations of 80—90 mcg/ml occur 2—6 hours after a single 1 g dose of clofibrate. Plasma concentrations of 160—200 mcg/mL are attained at steady-state in healthy volunteers taking 1 g bid. Clofibric acid is 98% protein-bound and is distributed only into the extracellular space. Serum triglyceride levels decrease within 2—5 days, with maximum clinical effect reached after 21 days. Clofibric acid is excreted in the urine, 20% unchanged and 70% as a glucuronide conjugate. Plasma half-life after a single dose in patients with normal renal and hepatic functions ranges from 12—35 hours. Clofibrate clearance is reduced by about 50% in cirrhosis.
Metabolism of diazepam is primarily hepatic and involves demethylation (involving primarily CYP2C19 and CYP3A4) and 3-hydroxylation (involving primarily CYP3A4). Diazepam is extensively metabolized to one major active metabolite desmethyldiazepam and two minor active metabolites temazepam (3-hydroxydiazepam) and oxazepam (3-hydroxy-N-diazepam), with half-lives of 30—100 hours, 9.5—12 hours, and 5—15 hours, respectively. At therapeutic doses, desmethyldiazepam is found in plasma at concentrations equivalent to those of diazepam. Oxazepam and temazepam plasma concentrations are usually undetectable. The half-life of diazepam is 30—60 hours. These metabolites are subsequently glucuronidated and excreted in the urine.
Now the reason why all these drugs are contraindicated in renal failure patients is simple because they are not able to be eliminated the drug and their active metabolites from the body via the urine. So with repeated dosing and the inability to eliminate the drug from the body, the drug starts to accumulate in the body to toxic levels.
