Nelfinavir mesylate (Viracept, formally AG1343) is a potent and orally bioavailable human immunodeficiency virus (HIV) type 1 (HIV-1) protease inhibitor (K i ‫؍‬ 2 nM) and is being widely prescribed in combination with HIV reverse transcriptase inhibitors for the treatment of HIV infection. The current studies evaluated the presence of metabolites circulating in plasma following the oral administration of nelfinavir to healthy volunteers and HIV-infected patients, as well as the levels in plasma and antiviral activities of these metabolites. The results showed that the parent drug was the major circulating chemical species, followed in decreasing abundance by its hydroxy-t-butylamide metabolite (M8) and 3-methoxy-4-hydroxynelfinavir (M1). Antiviral assays with HIV-1 strain RF-infected CEM-SS cells showed that the 50% effective concentrations (EC 50 ) of nelfinavir, M8, and M1 were 30, 34, and 151 nM, respectively, and that the corresponding EC 50 against another HIV-1 strain, IIIB, in MT-2 cells were 60, 86, and 653 nM. Therefore, apparently similar in vitro antiviral activities were demonstrated for nelfinavir and M8, whereas an approximately 5-to 11-fold-lower level of antiviral activity was observed for M1. The active metabolite, M8, showed a degree of binding to human plasma proteins similar to that of nelfinavir (ca. 98%). Concentrations in plasma of nelfinavir and its metabolites in 10 HIV-positive patients receiving nelfinavir therapy (750 mg three times per day) were determined by a liquid chromatography tandem mass spectrometry assay. At steady state (day 28), the mean plasma nelfinavir concentrations ranged from 1.73 to 4.96 M and the M8 concentrations ranged from 0.55 to 1.96 M, whereas the M1 concentrations were low and ranged from 0.09 to 0.19 M. In conclusion, the findings from the current studies suggest that, in humans, nelfinavir forms an active metabolite circulating at appreciable levels in plasma. The active metabolite M8 may account for some of the antiviral activity associated with nelfinavir in the treatment of HIV disease.

Page 1090, column 1, lines 1 to 5: "did not show any. .. or its metabolites" should read "showed no significant differences in exposure to either the parent drug or its metabolites between the first dose and steady state (Table 3); however, this analysis was not designed or powered to rule out modest changes in clearance or exposure, and the trend for increased M8-to-nelfinavir concentration ratio on day 28 may reflect modest induction of metabolism during multiple dosing."

After oral administration of 14C-labeled idebenone (14C-CV-2619) to rats, the plasma 14C level reached a plateau at 15 min, which persisted till 8 h and then decreased with a half-life of 4.5 h. In dogs, after oral dosing, the plasma 14C peaked at 15 min, followed by biophysical decline with half-lives of 2.2 and 15.4 h. The plasma of both animals contained mostly metabolites, with a small amount of unchanged CV-2619, which was greater than 90% protein-bound. In rats given 14C-CV-2619 orally or intravenously, 14C was distributed widely in tissues, with relatively high concns. in the gut, liver and kidney. CV-2619 readily entered the rat brain to undergo subcellular distribution with a significant amount localized in mitochondria. The concn. of 14C in rat fetus was low, as was that in the milk. Oral 14C-CV-2619 was eliminated by rats and dogs mostly as metabolites within 48 h. In rats, more was excreted in urine than in feces, whereas in dogs excretion by these two routes was almost equal. Enterohepatic cycling of biliary 14C occurred in rats. Repeated oral ingestions of 14C-CV-2619 to rats resulted in no accumulation of 14C. The metabolites found in rats and dogs were QS-10, QS-8, QS-6 and QS-4 formed by oxidative shortening of the side chain of CV-2619, and desmethylated CV-2619 and QS-4. Glucuronides and sulfates of the dihydro (quinol) derivatives of the above metabolites were also detected. Dihydro QS-4 sulfate was the major metabolite in plasma and urine of both animals, while dihydro QS-10 glucuronide was predominant in rat bile.

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