Clinical Implications of Drug Metabolism and Transport

Clinical Practice: Anti-retrovirals

Lopinavir/Ritonavir

Antiretroviral drug combination: Lopinavir/Ritonavir. The tablet contains both drugs for a specific reason related to drug metabolism and transport.

Reason for Combining Lopinavir and Ritonavir

Lopinavir is a substrate of P-glycoprotein and cytochrome P450 3A4 (CYP3A4). Lopinavir is metabolized by enzymes in the gut and liver, specifically CYP3A4. Additionally, it is a substrate of P-glycoprotein, which effluxes the drug out of the gut and liver, resulting in low bioavailability and low exposure of Lopinavir in the systemic circulation.

Ritonavir is added to lopinavir, not for its antiviral effects, but because it inhibits P-glycoprotein and CYP3A4.

• P-glycoprotein Inhibition: Ritonavir blocks P-glycoprotein from functioning, preventing it from effluxing Lopinavir, allowing Lopinavir to enter the body more freely.
• CYP3A4 Inhibition: Ritonavir inhibits CYP3A4, reducing the metabolism of Lopinavir, thus increasing its systemic exposure.

This strategy is considered a clever way to improve drug bioavailability by manipulating drug transport and metabolism.

Exploiting Transporter Inhibition

There have been attempts to use similar strategies to get drugs into the central nervous system (CNS) by blocking P-glycoprotein. However, these attempts have been less successful.
The general principle is that to move drugs into different compartments, it may be necessary to inhibit transporters and enzymes to facilitate drug entry and prevent efflux.