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

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 [7]

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 [8]:

• 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 [9]. 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.

Reference

1. von Moltke LL, Greenblatt DJ, Schmider J, Wright CE, Harmatz JS and Shader RI. In vitro approaches to predicting drug interactions in vivo. Biochemical Pharmacology 1998;55:113-122.



2. Venkatakrishnan K, von Moltke LL and Greenblatt DJ. Human drug metabolism and the cytochromes P450: application and relevance of in vitro models. Journal of Clinical Pharmacology 2001;41:1149-1179.



3. von Moltke LL, Greenblatt DJ, Grassi JM, Granda BW, Duan SX, Fogelman SM, Daily JP, Harmatz JS and Shader RI. Protease inhibitors as inhibitors of human cytochromes P450: high risk associated with ritonavir. Journal of Clinical Pharmacology 1998;38:106-111.



4. Greenblatt DJ, von Moltke LL, Harmatz JS, Durol ALB, Daily JP, Graf JA, Mertzanis P, Hoffman JL and Shader RI. Differential impairment of triazolam and zolpidem clearance by ritonavir. Journal of Acquired Immune Deficiency Syndromes 2000;24:129-136.



5. Venkatakrishnan K, von Moltke LL, Obach RS and Greenblatt DJ. Microsomal binding of amitriptyline: effect on estimation of enzyme kinetic parameters in vitro. Journal of Pharmacology and Experimental Therapeutics 2000;293:343-350.



6. Gibbs MA, Kunze KL, Howald WN and Thummel KE. Effect of inhibitor depletion on inhibitory potency: tight binding inhibition of CYP3A by clotrimazole. Drug Metab Dispos 1999;27:596-599.



7. von Moltke LL, Durol ALB, Duan SX and Greenblatt DJ. Potent mechanism-based inhibition of human CYP3A in vitro by amprenavir and ritonavir: comparison with ketoconazole. European Journal of Clinical Pharmacology 2000;56:259-261.



8. Silverman R. Mechanism-based enzyme inactivators. Methods in Enzymology 1995;249:240-283.



9. Greenblatt DJ, von Moltke LL, Harmatz JS, Durol ALB, Daily JP, Graf JA, Mertzanis P, Hoffman JL and Shader RI. Alprazolam-ritonavir interaction: implications for product labeling. Clinical Pharmacology and Therapeutics 2000;67:335-341.



10. Kim RB, Fromm MF, Wandel C, Leake B, Wood AJJ, Roden DM and Wilkinson GR. The drug transporter P-glycoprotein limits oral absorption and brain entry of HIV-1 protease inhibitors. Journal of Clinical Investigation 1998;101:289-294.



11. Schuetz EG and Schinkel AH. Drug disposition as determined by the interplay between drug-transporting and drug-metabolizing systems. J Biochem Molecular Toxicology 1999;13:219-222.



12. Störmer E, von Moltke LL, Perloff MD and Greenblatt DJ. P-glycoprotein interactions of nefazodone and trazodone in cell culture. Journal of Clinical Pharmacology 2001;41:708-714.



13. 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.



14. Perloff MD, von Moltke LL, Stšrmer E, Shader RI and Greenblatt DJ. Saint John's wort: An in vitro analysis of P-glycoprotein induction due to extended exposure. British Journal of Pharmacology 2001;134:1601-1608.



15. 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.