Protease inhibitor-induced nausea and vomiting is attenuated by a peripherally acting, opioid-receptor antagonist in a rat model

We observed that 24 to 48 hr after administration of oral ritonavir 20 mg/kg, kaolin consumption increased significantly in rats (P < 0.01). This increase was attenuated by pretreatment with an intraperitoneal injection of methylnaltrexone (0.3–3.0 mg/kg) in a dose dependent manner (P < 0.01) and also with naloxone (0.1–0.3 mg/kg) (P < 0.01). The areas under the curve for kaolin intake from time 0 to 120 hr were significantly reduced after administration of the opioid antagonists. Food intake was not significantly affected. Plasma naltrexone levels were measured after methylnaltrexone injection, and no detectable levels were found, indicating that methylnaltrexone was not demethylated in our experimental paradigm.These results suggest that methylnaltrexone may have potential clinical utility in reducing nausea and vomiting in HIV patients who take ritonavir.Infection with the human immunodeficiency virus (HIV), which may progress to acquired immune deficiency syndrome (AIDS), is a deadly disease that affects many millions of people worldwide [1,2]. If patients are not treated in a timely fashion, the disease can cause morbidity and lead to death because of immune dysfunction and opportunistic infections. To reduce viral loads and improve life expectancy, treatment guidelines require that patients comply with drug regimens for an extended period of time [3,4]. The main obstacles to such compliance are treatment-induced adverse effects. Adverse effects not only deteriorate quality of life, but negatively affect compliance [5]. Nausea and vomiting are examples of drug-induced adverse effects that may affect compliance [4,6,7].Protease inhibitors are commonly used potent anti-HIV drugs. Drugs in this class, especially ritonavir, induce nausea and vomiting [8]. Ritonavir is used in anti-HIV therapy as an adjuvant to other protease inhibitors because it inhibits the hepatic CYP 3A enzyme, thereby increasing the bioavailability and plasma concentration of other antiviral a