Twenty-six years of HIV science: an overview of anti-HIV drugs metabolism

From the identification of HIV as the agent causing AIDS, to the development of effective antiretroviral drugs, the scientific achievements in HIV research over the past twenty-six years have been formidable. Currently, there are twenty-five anti-HIV compounds which have been formally approved for clinical use in the treatment of AIDS. These compounds fall into six categories: nucleoside reverse transcriptase inhibitors (NRTIs), nucleotide reverse transcriptase inhibitors (NtRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), cell entry inhibitors or fusion inhibitors (FIs), co-receptor inhibitors (CRIs), and integrase inhibitors (INIs). Metabolism by the host organism is one of the most important determinants of the pharmacokinetic profile of a drug. Formation of active or toxic metabolites will also have an impact on the pharmacological and toxicological outcomes. Therefore, it is widely recognized that metabolism studies of a new chemical entity need to be addressed early in the drug discovery process. This paper describes an overview of the metabolism of currently available anti-HIV drugs.Da identificação do HIV como o agente causador da AIDS, ao desenvolvimento de fármacos antirretrovirais eficazes, os avanços científicos na pesquisa sobre o HIV nos últimos vinte e seis anos foram marcantes. Atualmente, existem vinte e cinco fármacos anti-HIV formalmente aprovados pelo FDA para utilização clínica no tratamento da AIDS. Estes compostos são divididos em seis classes: inibidores nucleosídeos de transcriptase reversa (INTR), inibidores nucleotídeos de transcriptase reversa (INtTR), inibidores não-nucleosídeos de transcriptase reversa (INNTR), inibidores de protease (IP), inibidores da entrada celular ou inibidores de fusão (IF), inibidores de co-receptores (ICR) e inibidores de integrase (INI). O metabolismo consiste em um dos maiores determinantes do perfil farmacocinético de um fármaco. A formação de metabólitos ativos ou tóxicos terá impacto nas respostas farmacológicas ou toxicológicas do fármaco. Portanto, é amplamente reconhecido que estudos do metabolismo de uma nova entidade química devem ser realizados durante as fases iniciais do processo de desenvolvimento de fármacos. Este artigo descreve uma abordagem do metabolismo dos fármacos anti-HIV atualmente disponíveis na terapêutica

Binding of Drugs With a Quaternary Ammonium Group to alpha-1 Acid Glycoprotein and Asialo alpha-1 Acid Glycoprotein

The interaction of eight mono- and four bisquaternary ammonium compounds with alpha-1 acid glycoprotein and its desialylated derivative was investigated. Protein binding was performed in vitro by equilibrium dialysis at 37 degrees C. The simple monoquaternary ammonium compounds tributylmethylammonium, tripropylmethylammonium, triethylmethylammonium and procainethobromide were not appreciably bound (unbound fraction greater than 0.99). Excellent negative correlations of unbound fraction and the log of the octanol/Krebs' partition coefficient were obtained for thiazinamium, N-methylimipramine, N-methyldeptropine and d-tubocurarine, both for alpha-1 acid glycoprotein (r = -0.99) and asialo alpha-1 acid glycoprotein (r = -0.94). Bisquaternary ammonium compounds, with the exception of hexafluorenium, were only poorly bound. Our binding data on N-methyl-deptropine, N-methylimipramine and thiazinamium reveal that these compounds are more avidly bound to alpha-1 acid glycoprotein than to albumin, in spite of their polar character. The interaction of N-methyldeptropine with alpha-1 acid glycoprotein was studied in more detail. Scatchard plots revealed the presence of two classes of binding sites. N-Methyldeptropine could effectively be displaced by imipramine from its high-affinity binding site. This points to the presence of a common high-affinity binding site for tertiary and quaternary ammonium compounds on alpha-1 acid glycoprotei