Mechanisms for Pharmacokinetic and Pharmacodynamic Interactions Between Psychoactive and Antiretroviral Medications
David J. Greenblatt, MD
Tufts University School of Medicine, and Tufts-New England Medical Center, Boston, Massachusetts
Antiretroviral drugs complicate the management of drug abusers for several reasons:
- Antiretrovirals can influence their own kinetics.
- They can enhance the abuseability and toxicity of abused drugs.
- They can enhance the abuseability and toxicity of agents used to treat drug abuse.
- They can diminish the effect of agents used to treat substance abuse or psychiatric disorders.
The dilemma facing pharmacologists studying these interactions is that there are too many interactions to be studied clinically. One solution to this dilemma is refining In-vitro methods to study drug-drug interactions [1,2].
What can be learned from In-vitro studies?
Dr. Greenblatt began his consideration of In-vitro studies involving antiretrovirals and psychotropic agents with the example of triazolam, a triazolo-benzodiazepine hypnotic drug. Pharmacologic research predicted that the chance of interactions with triazolam is high if the plasma concentrations of the inhibitor greatly exceed the 50% inhibitory concentration (IC50). That prediction proved true in a study assessing ritonavir-triazolam interactions [3,4]. Ritonavir significantly increased and prolonged the concentration of triazolam. Increased triazolam levels can significantly elevate beta EEG amplitude and produce excessive sedation.
To further demonstrate interactions between antiretrovirals and psychotropic agents, Dr. Greenblatt described a four-part study involving trazadone and ritonavir at a dose of ritonavir high enough to inhibit cytochrome P450 (CYP) 3A but not to induce it.
Plan for a trazadone-ritonavir interaction study
||200 mg x 4
||200 mg x 4
The study showed that ritonavir significantly increased the area under the concentration-time curve (AUC) of trazadone, whereas trazadone did not affect plasma levels of ritonavir.
Potential problems with In-vitro studies
Dr. Greenblatt noted that these studies show how In-vitro data can yield reasonable clinical predictions. But certain factors may complicate the analysis of In-vitro interaction studies:
- Substrate/inhibitor binding and depletion [5,6]
- Mechanism-based inhibition 
As they do in In-vivo, protein concentrations can lower drug concentrations in In-vitro. In-vitro protein concentrations influence:
- Substrate kinetic parameters and estimation of inhibitory potency
- Predictions of clinical drug interactions based on In-vitro data
Dr. Greenblatt specified two operational correlates of mechanism-based inhibition :
- Preincubation, in which the inhibitor is exposed to microsomes and cofactors before the addition of substrate, increases the potency of a mechanism-based inhibitor
- Preincubation reduces inhibitor potency
The clinical implications of mechanism-based inhibition have not been established, Dr. Greenblatt added.
Two clinical issues that may complicate interpretation of In-vitro drug interaction studies are the role of physiologic variables and mixed induction and inhibition of CYP3A by a single drug. Ritonavir, for example, both inhibits and induces CYP3A. As a result, in the short term ritonavir inhibits the metabolism of the anxiolytic alprazolam . But over the long term ritonavir induces alprazolam metabolism.
Drug transporter and animal models
Much recent attention has focused on the role of drug transporters such as P-glycoprotein (P-gp) on the disposition of antiretroviral drugs [10,11]. Because P-gp is expressed in intestinal epithelial cells, in liver and kidney, and at various blood-tissue barriers, its expression could limit antiretroviral entry into critical compartments and may especially limit the systemic availability of protease inhibitors (PIs).
Dr. Greenblatt noted that there are In-vitro models for P-gp interactions, including Caco-2 cells and LS-180 intestinal cells, a human colon carcinoma cell line [12-15]. In the LS-180 system, the PIs ritonavir, nelfinavir, and amprenavir strongly induce P-gp expression [13-15].
Animal models can also be used to understand drug interactions. Ritonavir at a dose of 20 mg/kg significantly induced CYP3A in male Sprague-Dawley rats. Sprague-Dawley rats have also been used to measure ritonavir activity at the blood-brain barrier and in intestinal mucosa. Dr. Greenblatt anticipates that this animal model could be useful in further antiretroviral studies.
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- Perloff MD, von Moltke LL, Marchand JE and Greenblatt DJ. Ritonavir induces P-glycoprotein expression, multidrug resistance-associated protein (MRP1) expression, and drug transporter-mediated activity in a human intestinal cell line. Journal of Pharmaceutical Sciences 2001;90:1829-1837.
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- Perloff MD, von Moltke LL, Fahey JM, Daily JP and Greenblatt DJ. Induction of P-glycoprotein expression by HIV protease inhibitors in cell culture. AIDS 2000;14:1287-1289.