Comparison of a new orally potent tripeptide HIV‐1 protease inhibitor (anti‐aids drug) based on pharmacokinetic characteristics in rats after intravenous and intraduodenal administrations

  title={Comparison of a new orally potent tripeptide HIV‐1 protease inhibitor (anti‐aids drug) based on pharmacokinetic characteristics in rats after intravenous and intraduodenal administrations},
  author={Akiko Kiriyama and T Mimoto and Sumitsugu Kisanuki and Yoshiaki Kiso and Kanji Takada},
  journal={Biopharmaceutics \& Drug Disposition},
Recently, a series of KNI compounds such as KNI‐227 and KNI‐272 has been synthesized and shows potent and selective HIV‐1 protease inhibitory activity in vitro. In this study, we developed an HPLC assay system for KNI‐227 and KNI‐272 in rat plasma and examined the pharmacokinetic characteristics in rats after both intravenous (i.v.) and intraduodenal (i.d.) administrations to obtain the disposition characteristics and bioavailabilities of these new anti‐AIDS drugs. After i.v. administration of… 
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Plasma pharmacokinetics and urinary and biliary excretion of a new potent tripeptide HIV‐1 protease inhibitor, KNI‐272, in rats after intravenous administration
The pharmacokinetic characteristics of KNI‐272, a potent and selective HIV‐1 protease inhibitor, were evaluated in rats after intravenous (IV) administration and showed that the disposition of K NI‐272 in the rat plasma is linear within the dose range from 1.0 to 10.0mg kg−1.
Absorption of new HIV‐1 protease inhibitor, KNI‐272, after intraduodenal and intragastric administrations to rats: Effect of solvent
For the development of an oral dosage form of KNI‐272, a non‐ionic surfactant that dissolves in the duodenum or small intestine and that enhances the absorption of this drug from the gastrointestinal tract into the enterocytes is needed.
Physiologically based pharmacokinetics of KNI‐272, a tripeptide HIV‐1 protease inhibitor
A physiologically based pharmacokinetic (PBPK) model was developed for KNI‐272 in rats in which concentration‐dependent nonlinear hepatic metabolism (Michaelis‐Menten type metabolism) was considered and it was demonstrated that the terminal elimination phase was proportional to the dose at lower doses.
Pharmacokinetics of the Protease Inhibitor KNI-272 in Plasma and Cerebrospinal Fluid in Nonhuman Primates after Intravenous Dosing and in Human Immunodeficiency Virus-Infected Children after Intravenous and Oral Dosing
It appears that KNI-272 will play a limited role in the treatment of HIV-infected children and the pharmacokinetic profile of the drug may limit the drug’s efficacy in vivo.
Metabolic Characterization of a Tripeptide Human Immunodeficiency Virus Type 1 Protease Inhibitor, KNI-272, in Rat Liver Microsomes
From these results and reported physiological parameters, the liver was considered to be the main organ which takes part in the metabolic elimination of KNI-272 and it was determined to be metabolized mainly by the CYP3A isoform.
Progress in the discovery of orally bioavailable inhibitors of HIV protease
This Perspective contrasts the preclinical pharmacokinetic parameters of a variety of HIV protease inhibitors with significant oral bioavailability with those with high oral Cmax/in vitro EC50 ratios.
Design and synthesis of substrate-based peptidomimetic human immunodeficiency virus protease inhibitors containing the hydroxymethylcarbonyl isostere.
  • Y. Kiso
  • Biology, Chemistry
  • 1996
The human immunodeficiency (HIV) codes for an aspartic protease known to be essential for retroviral maturation and replication. The HIV protease can recognize Phe-Pro and Tyr-Pro sequences as the
Design and synthesis of HIV protease inhibitors containing allophenylnorstatine as a transition-state mimic.
  • Y. Kiso
  • Biology
    Advances in experimental medicine and biology
  • 1995
The human immunodeficiency virus type-1 codes for a virus-specific aspartic protease responsible for processing the gag and gag-pol polyproteins and for the proliferation of the retrovirus, which provided a basis for the rational design of selective HIV protease-targeted drugs for the treatment of AIDS and related complex.


Pharmacokinetic study of a tripeptide HIV‐1 protease inhibitor, KNI‐174, in rats after intravenous and intraduodenal administrations
An HPLC assay system is developed and examined the pharmacokinetics of KNI‐174 in rats using this assay method after both intravenous and intraduodenal administrations to obtain the disposition characteristics and bioavailability of this new anti‐AIDS drug.
In vitro anti-human immunodeficiency virus (HIV) activities of transition state mimetic HIV protease inhibitors containing allophenylnorstatine
Two compounds, K NI-227 and KNI-272, which were highly potent against HIV protease with little inhibition of other aspartic proteases, showed the most potent activity against the infectivity and cytopathic effect of a wide spectrum of HIV strains.
Antiviral and pharmacokinetic properties of C2 symmetric inhibitors of the human immunodeficiency virus type 1 protease.
A series of novel, symmetric inhibitors of HIV protease designed to match the C2 symmetric structure of the active site of the enzyme revealed broad-spectrum activity against both HIV types 1 and 2, including azidothymidine-resistant HIV, in a variety of transformed and primary human cell lines.
Kynostatin (KNI)-227 and -272, highly potent anti-HIV agents: conformationally constrained tripeptide inhibitors of HIV protease containing allophenylnorstatine.
Conformationally constrained tripeptide derivatives, kynostatin (KNI)-227 and -272, exhibited highly potent antiviral activities against a wide spectrum of HIV isolates, indicating that KNI-227 and K NI-272 are promising candidates as selective anti-AIDS drugs.
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  • Biology, Chemistry
    AIDS research and human retroviruses
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This review summarizes the strategies and multidisciplinary efforts that have been applied to date to the identification of specific inhibitors of this critical viral enzyme, including rationally designed peptide substrate analogs, compounds conceived from tertiary structure information on the enzyme and natural products.
Human immunodeficiency virus protease: A target for aids therapy
Peptide analogues containing transition‐state mimics were synthesized and shown to inhibit the activity of the purified HIV protease in vitro to various extents, most interestingly, the most potent inhibitors were shown to effectively block the prote enzyme in HIV‐infected cells and to impair the viral life cycle.
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