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Understanding PI boosting
| Last updated: 25.08.04 |
Cytochrome P450
Protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) are extensively metabolised by the cytochrome P450 system, as are many other drugs.
Cytochrome P450 is a group of enzymes found in the liver and the gut which have a number of functions in the human body. One function is the breakdown and clearance of medications and other chemicals.
Taking two or more drugs which are metabolised by cytochrome P450 may produce a drug interaction affecting concentrations of one or both drugs, and causing side-effects or undermining the clinical efficacy of the medication(s).
The activity of cytochrome P450 differs between individuals and between populations. Small genetic variations can affect how much particular enzymes are expressed, and thus how quickly the drug is metabolised.
Cytochrome P450 enzymes which derive from a particular gene are called isoforms. Based on the similarity of their chemical make-up, isoforms are divided into families, subfamilies and individual genes. Enzyme variants are described through a numbering and lettering system which reflects their chemical and genetic structure.
CYP3A4 is one particular metabolic pathway which is very important to many medications and other substances.
Protease inhibitors are metabolised through the cytochrome P450 system and CYP3A4 in particular. Drugs which induce (speed up) the activity of CYP3A4, such as the TB drug rifampicin, can reduce exposure to the PIs.
CYP3A4 has a complex interrelationship with PIs. It binds well with PIs and starts to break them down. But as this occurs, the drug ‘damages’ and inhibits the activity of CYP3A4.
This means that PIs can slow the processing of other medications which are metabolised through CYP3A4. Ritonavir is a particularly potent inhibitor of CYP3A4, hence its role in PI boosting.
P-glycoprotein
Drug metabolism is also affected by p-glycoprotein – a transport protein which protects cells from poisons. P-glycoprotein is important in PI metabolism because it treats PIs as if they were poisons and pumps them out of cells.
Ritonavir inhibits the activity of p-glycoprotein, as do, to a lesser extent, saquinavir, nelfinavir and indinavir.26 When taken with another PI, ritonavir can increase cellular exposure to the other PIs.
An ideal alternative agent to ritonavir for PI boosting would also slow the activity of p-glycoprotein.
Protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) are extensively metabolised by the cytochrome P450 system, as are many other drugs.
Cytochrome P450 is a group of enzymes found in the liver and the gut which have a number of functions in the human body. One function is the breakdown and clearance of medications and other chemicals.
Taking two or more drugs which are metabolised by cytochrome P450 may produce a drug interaction affecting concentrations of one or both drugs, and causing side-effects or undermining the clinical efficacy of the medication(s).
The activity of cytochrome P450 differs between individuals and between populations. Small genetic variations can affect how much particular enzymes are expressed, and thus how quickly the drug is metabolised.
Cytochrome P450 enzymes which derive from a particular gene are called isoforms. Based on the similarity of their chemical make-up, isoforms are divided into families, subfamilies and individual genes. Enzyme variants are described through a numbering and lettering system which reflects their chemical and genetic structure.
CYP3A4 is one particular metabolic pathway which is very important to many medications and other substances.
Protease inhibitors are metabolised through the cytochrome P450 system and CYP3A4 in particular. Drugs which induce (speed up) the activity of CYP3A4, such as the TB drug rifampicin, can reduce exposure to the PIs.
CYP3A4 has a complex interrelationship with PIs. It binds well with PIs and starts to break them down. But as this occurs, the drug ‘damages’ and inhibits the activity of CYP3A4.
This means that PIs can slow the processing of other medications which are metabolised through CYP3A4. Ritonavir is a particularly potent inhibitor of CYP3A4, hence its role in PI boosting.
P-glycoprotein
Drug metabolism is also affected by p-glycoprotein – a transport protein which protects cells from poisons. P-glycoprotein is important in PI metabolism because it treats PIs as if they were poisons and pumps them out of cells.
Ritonavir inhibits the activity of p-glycoprotein, as do, to a lesser extent, saquinavir, nelfinavir and indinavir.26 When taken with another PI, ritonavir can increase cellular exposure to the other PIs.
An ideal alternative agent to ritonavir for PI boosting would also slow the activity of p-glycoprotein.