scholarly journals Metabolic Characterization of a Tripeptide Human Immunodeficiency Virus Type 1 Protease Inhibitor, KNI-272, in Rat Liver Microsomes

1999 ◽  
Vol 43 (3) ◽  
pp. 549-556 ◽  
Author(s):  
Akiko Kiriyama ◽  
Tomoyuki Nishiura ◽  
Hirokazu Yamaji ◽  
Kanji Takada
Keyword(s):  
Human Immunodeficiency Virus ◽  
Protease Inhibitor ◽  
Rat Liver ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Liver Microsomes ◽  
Tissue Blood Flow ◽  
Rat Liver Microsomes ◽  
Immunodeficiency Virus

ABSTRACT KNI-272 is a tripeptide protease inhibitor for treating human immunodeficiency virus type 1 (HIV-1). In in vitro stability studies using rat tissue homogenates, KNI-272 concentrations in the liver, kidney, and brain decreased significantly with time. Moreover, in tissue distribution studies, KNI-272 distributed highly to the liver, kidney, and small intestine in vivo. From these results and reported physiological parameters such as the tissue volume and tissue blood flow rate, we considered the liver to be the main organ which takes part in the metabolic elimination of KNI-272. Then the hepatic metabolism of KNI-272 was more thoroughly investigated by using rat liver microsomes. KNI-272 was metabolized in the rat liver microsomes, and five metabolites were found. The initial metabolic rate constant (k metabolism) tended to decrease when the KNI-272 concentration in microsomal suspensions increased. The calculated Michaelis-Menten constant (Km) and the maximum velocity of KNI-272 metabolism (V max), after correction for the unbound drug concentration, were 1.12 ± 0.09 μg/ml (1.68 ± 0.13 μM) and 0.372 ± 0.008 μg/mg of protein/min (0.558 ± 0.012 nmol/mg of protein per min), respectively. The metabolic clearance (CLint,metabo), calculated asV max/Km , was 0.332 ml/mg of protein per min. Moreover, by using selective cytochrome P-450 inhibitors and recombinant human CYP3A4 fractions, KNI-272 was determined to be metabolized mainly by the CYP3A isoform. In addition, ketoconazole, a representative CYP3A inhibitor, inhibited KNI-272 metabolism competitively, and the inhibition constant(Ki) was 4.32 μM.

scholarly journals TMC310911, a Novel Human Immunodeficiency Virus Type 1 Protease Inhibitor, ShowsIn Vitroan Improved Resistance Profile and Higher Genetic Barrier to Resistance Compared with Current Protease Inhibitors

2011 ◽  
Vol 55 (12) ◽  
pp. 5723-5731 ◽  
Author(s):  
Inge Dierynck ◽  
Herwig Van Marck ◽  
Marcia Van Ginderen ◽  
Tim H. M. Jonckers ◽  
Madhavi N. L. Nalam ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Protease Inhibitor ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Clinical Isolates ◽  
Immunodeficiency Virus ◽  
Hiv 1 ◽  
Selection Of

ABSTRACTTMC310911 is a novel human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI) structurally closely related to darunavir (DRV) but with improved virological characteristics. TMC310911 has potent activity against wild-type (WT) HIV-1 (median 50% effective concentration [EC50], 14 nM) and a wide spectrum of recombinant HIV-1 clinical isolates, including multiple-PI-resistant strains with decreased susceptibility to currently approved PIs (fold change [FC] in EC50, >10). For a panel of 2,011 recombinant clinical isolates with decreased susceptibility to at least one of the currently approved PIs, the FC in TMC310911 EC50was ≤4 for 82% of isolates and ≤10 for 96% of isolates. The FC in TMC310911 EC50was ≤4 and ≤10 for 72% and 94% of isolates with decreased susceptibility to DRV, respectively.In vitroresistance selection (IVRS) experiments with WT virus and TMC310911 selected for mutations R41G or R41E, but selection of resistant virus required a longer time than IVRS performed with WT virus and DRV. IVRS performed with r13025, a multiple-PI-resistant recombinant clinical isolate, and TMC310911 selected for mutations L10F, I47V, and L90M (FC in TMC310911 EC50= 16). IVRS performed with r13025 in the presence of DRV required less time and resulted in more PI resistance-associated mutations (V32I, I50V, G73S, L76V, and V82I; FC in DRV EC50= 258). The activity against a comprehensive panel of PI-resistant mutants and the limitedin vitroselection of resistant viruses under drug pressure suggest that TMC310911 represents a potential drug candidate for the management of HIV-1 infection for a broad range of patients, including those with multiple PI resistance.

scholarly journals Results of 2 Years of Treatment with Protease‐Inhibitor–Containing Antiretroviral Therapy in Dutch Children Infected with Human Immunodeficiency Virus Type 1

2002 ◽  
Vol 34 (7) ◽  
pp. 1008-1016 ◽  
Author(s):  
Annemarie M. C. van Rossum ◽  
Sibyl P. M. Geelen ◽  
Nico G. Hartwig ◽  
Tom F. W. Wolfs ◽  
Corry M. R. Weemaes ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Antiretroviral Therapy ◽  
Protease Inhibitor ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Immunodeficiency Virus ◽  
Dutch Children

scholarly journals Fitness of Human Immunodeficiency Virus Type 1 Protease Inhibitor-Selected Single Mutants

Virology ◽  
2000 ◽  
Vol 275 (2) ◽  
pp. 318-322 ◽  
Author(s):  
Javier Martinez-Picado ◽  
Anu V. Savara ◽  
Lijia Shi ◽  
Lorraine Sutton ◽  
Richard T. D'Aquila
Keyword(s):  
Human Immunodeficiency Virus ◽  
Protease Inhibitor ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Immunodeficiency Virus

scholarly journals Association of Saquinavir Plasma Concentrations with Side Effects but Not with Antiretroviral Outcome in Patients Infected with Protease Inhibitor-Susceptible Human Immunodeficiency Virus Type 1

2007 ◽  
Vol 51 (9) ◽  
pp. 3264-3272 ◽  
Author(s):  
Jörn Lötsch ◽  
Sebastian Harder ◽  
Martin Stürmer ◽  
Hans-Wilhelm Doerr ◽  
Gerd Geisslinger ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Side Effects ◽  
Protease Inhibitor ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Plasma Concentrations ◽  
Cd4 Counts ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT The objective of this study was to identify parameters among saquinavir pharmacokinetics, patients' demographics or comedications, to be addressed for improved personalized therapy. The presence of human immunodeficiency virus type 1 (HIV-1) RNA at therapy week 48 (principal target parameter), CD4 cell count at week 48, infections and side effects during 48 weeks, indicators of liver toxicity and lipid abnormalities at week 48, and a 12-h saquinavir plasma concentration-versus-time profile were assessed in 56 patients receiving saquinavir-ritonavir (1,000 and 100 mg, respectively) twice daily (44 therapy-naïve and 12 antiretrovirally pretreated patients) for association with saquinavir plasma concentrations, demographics, baseline values of target parameters, and coadministered antiretrovirals. Antiretroviral failure was observed in 8 of the 56 patients in whom HIV-1 RNA was detectable at week 48. This therapeutic failure was not associated with individual saquinavir pharmacokinetics. More likely, therapeutic failure was related to incidences interfering with antiretroviral therapy, causing therapy interruptions or incompliance. Weak associations were, however, seen between high maximum saquinavir plasma concentrations and both CD4 counts of ≥200 cells μl−1 at week 48 (P = 0.014) and constitutional side effects during 48 weeks (P = 0.002). However, patients with high CD4 counts and constitutional side effects were not identical (P = 0.53). Saquinavir therapeutic drug monitoring in patients infected with protease inhibitor-susceptible HIV-1 taking saquinavir-ritonavir (1,000 and 100 mg, respectively) is not demanded for improving the antiretroviral effect. It may be contemplated in cases with constitutional side effects or low CD4 counts with weak immune responses.

scholarly journals Resistance testing in children changing human immunodeficiency virus type 1 protease inhibitor

2002 ◽  
Vol 21 (3) ◽  
pp. 214-220 ◽  
Author(s):  
JEAN SERVAIS ◽  
MARC HAINAUT ◽  
VÉRONIQUE SCHMITZ ◽  
PHILIP MAES ◽  
KATRIEN FRANSEN ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Protease Inhibitor ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Resistance Testing ◽  
Immunodeficiency Virus
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