Case 1: Discussion

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This case highlights several potentially serious drug interactions that can occur with commonly prescribed medications. The most frequent metabolic site of drug-drug interactions occurs at the cytochrome P450 enzyme system, an enzyme system found in the gastrointestinal epithelium and liver [1]. A number of medications can either induce or inhibit these enzymes. The HIV protease inhibitors generally function as inhibitors of the cytochrome P450 3A4 isozyme (CYP3A4). Among the protease inhibitors, ritonavir (Norvir) is the most potent inhibitor of the CYP3A4 enzyme. Ritonavir can also inhibit the activity of other isozymes including CYP2D6, an enzyme responsible for the metabolism of many psychoactive substances such as opiates and amphetamines. The ritonavir package insert lists specific medications that are considered contraindicated for use with ritonavir (Figure 1) [2]. In addition to those medications listed in the package insert, ritonavir can cause clinically-significant drug-drug interactions with a large number of medications [3,4].

Protease Inhibitors and Erectile Dysfunction Drugs

Ritonavir and other protease inhibitors are known to inhibit the metabolism and elimination of medications used for erectile dysfunction, namely sildenafil (Viagra), tadalafil (Cialis), and vardenafil (Levitra). In particular, ritonavir increases the sildenafil drug exposure 11-fold and the vardenafil drug exposure 49-fold (Figure 2) [5,6]. The resulting effect of the interaction of ritonavir and either sildenafil or vardenafil can include hypotension, syncope, visual changes, and prolonged erection. Therefore specific recommendations have been made regarding the use of medications used for erectile dysfunction any potent enzyme inhibitor, including ritonavir. Because the use of nitrates, such as nitroglycerin or amyl nitrate (also known as "poppers"), can lead to vasodilation, the combination of a protease inhibitor, a medication for erectile dysfunction, and a nitrate can be extremely dangerous.

Interaction of Ritonavir and Other Protease Inhibitors

Although ritonavir is often a cause of concern in potential adverse drug-drug interactions, it also has a beneficial role in increasing the blood concentration of certain protease inhibitors. The use of low doses of ritonavir combined with other protease inhibitors is often referred to as "pharmacokinetic enhancement" (Figure 3) [7]. Potential benefits of pharmacokinetic enhancement with ritonavir include (1) extending dosing intervals of other protease inhibitors, (2) decreasing pill burden, (3) enhancing activity of other protease inhibitors by maintaining higher levels above the EC 50 concentrations, and (4) overcoming the reduction in some protease inhibitor levels caused by concomitant use of nevirapine (Viramune) or efavirenz (Sustiva) [8].

Potential Impact on Absorption

In addition to the interactions that can occur at the cytochrome P450 level, medications that impair or enhance absorption of other medications can clearly cause significant drug-drug interactions. The older didanosine (Videx) preparations (tablets, powder preparation, and sachet) contain a calcium carbonate-based buffer that binds with and decreases absorption of numerous medications, including indinavir (Crixivan), ketoconazole (Nizoral), dapsone (Avlosulfone), and fluoroquinolone antimicrobials [9]. The newer Videx EC consists of an outer capsule that surrounds multiple enteric-coated beadlets and these beadlets contain the active didanosine ingredient. After the medication is swallowed, the outer capsule dissolves in the stomach, but the enteric-coated beadlets remain intact and are not dissolved by stomach acid (Figure 4). As the enteric-coated beadlets enter the small intestine, the enteric coating dissolves and the didanosine is absorbed in the upper small intestine. The Videx EC does not contain a buffer and thus is not known to decrease the absorption of other medications [10]. Currently, it is recommended that all preparations of didanosine (including the newer and older forms) should be taken on an empty stomach to achieve adequate blood levels.

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