Lipid - regulating drugs inhibitors

The protease inhibitors, especially ritonavir, are known to be strong inhibitors of the cytochrome P450 isoenzyme CYP3A4. The levels of statins metabolised by this isoenzyme (notably simvastatin, and to some extent atorvastatin) are therefore increased. See Lipid regulating drugs , (p.l086) for information on the metabolism of the individual statins. 

D. Effects on Carbohydrate and Lipid Metaboiism The use of protease inhibitors in HAART drug combinations has led to the development of disorders in carbohydrate and lipid metabolism. It has been suggested that this is due to the inhibition of lipid-regulating proteins which have active sites with structural homology to that of HIV protease. The syndrome includes hyperglycemia and insulin resistance or hyperlipidemia, with altered body fat distribution. Buffalo hump, gynecomastia, and truncal obesity may occur with facial and peripheral lipodystrophy. The syndrome has been observed with protease inhibitors used in HAART regimens, with an incidence of 30-50% and a median onset time of approximately 1 year s duration of treatment. 

Activators and inhibitors regulate not the amount of enzyme protein but the activity ( efficiency ) of that which is present. Two principal mechanisms of control are (i) competitive and (ii) allosteric. Competitive control (inhibition) occurs when a compound which is structurally similar to the true substrate binds to the active site of the enzyme. This is how a number of drugs and poisons bring about their effect. For example, a group of therapeutic drugs called statins are used to treat heart disease because by inhibiting a key enzyme called HMGCoA reductase, they reduce the hepatic synthesis of cholesterol and therefore the plasma concentration of that lipid. 

How drugs relate to other topics in the book— kinetics, enzyme inhibitors, membrane receptors, metabolic regulation, lipid synthesis, and signal transduction... 

However, not just CPT-I, but all CPT enzymes that use c>4oriasmic substrates are regulated by malonyl-CoA and inhibited by TDGA and etomoxir. Thus, these drugs will also interfere with peroxisomal oxidation and influence microsomal acyl-CoA utilizing pathways such as lipid s nithesis and lipid modification of proteins for export. In view of recent indications that non-mitochondrial acyl-CoA pools may influence membrane turnover, this may not be desirable, so inhibitors specific to CPT-I would be better. We have studied the kinetics and inhibition of two of the CPT family of enzymes as the first step towards finding differences that could be exploited to inhibit -oxidation without affecting peripheral function. 

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