Intracellular Accumulation of Human Immunodeficiency Virus Protease Inhibitors

ABSTRACT Intracellular accumulation of the protease inhibitors (PIs) saquinavir (SQV), ritonavir (RTV), and indinavir (IDV) was determined in 50 human immunodeficiency virus-positive patients. Following extraction, PIs were quantified by mass spectrometry. Paired plasma and intracellular samples were collected over a full dosing interval from patients (13 on SQV, 6 on RTV, 8 on IDV, 16 on SQV plus RTV, 7 on IDV plus RTV) with a plasma viral load of <400 copies/ml. Data were expressed as intracellular/plasma drug concentration ratios. A hierarchy of intracellular accumulation was demonstrated by the following medians: 9.45 for SQV > 1.00 for RTV > 0.51 for IDV. Coadministration of RTV did not boost ratios of SQV or IDV within the cell or in plasma, although absolute plasma and intracellular SQV concentrations were increased by RTV. Seven individuals receiving SQV in hard-gel capsule form (median, 32 months) had higher intracellular/plasma drug ratios than all other patients receiving SQV (median, 17.62 versus 4.83; P = 0.04), despite consistently low plasma SQV concentrations. How this occurs may provide insight into the mechanisms that limit adequate drug penetration into sanctuary sites.

[1]  J. Beijnen,et al.  Long-term suppression of viral replication despite low plasma saquinavir concentrations in the CHEESE Study. , 2002, British Journal of Clinical Pharmacology.

[2]  S. Repping,et al.  Pharmacokinetic Profiles of Nevirapine and Indinavir in Various Fractions of Seminal Plasma , 2001, Antimicrobial Agents and Chemotherapy.

[3]  S. Khoo,et al.  P-glycoprotein and transporter MRP1 reduce HIV protease inhibitor uptake in CD4 cells: potential for accelerated viral drug resistance? , 2001, AIDS.

[4]  S. Khoo,et al.  Differences in the intracellular accumulation of HIV protease inhibitors in vitro and the effect of active transport , 2001, AIDS.

[5]  J. Beijnen,et al.  P-glycoprotein limits oral availability, brain, and fetal penetration of saquinavir even with high doses of ritonavir. , 2001, Molecular pharmacology.

[6]  Stephen Taylor,et al.  Antiretroviral drug concentrations in semen of HIV-1 infected men , 2001, Sexually transmitted infections.

[7]  Peter L. Anderson,et al.  Pharmacological Basis for Concentration-Controlled Therapy with Zidovudine, Lamivudine, and Indinavir , 2001, Antimicrobial Agents and Chemotherapy.

[8]  L. Kingsley,et al.  Human immunodeficiency virus type 1 shedding pattern in semen correlates with the compartmentalization of viral Quasi species between blood and semen. , 2000, The Journal of infectious diseases.

[9]  G R Wilkinson,et al.  Pharmacological inhibition of P-glycoprotein transport enhances the distribution of HIV-1 protease inhibitors into brain and testes. , 2000, Drug metabolism and disposition: the biological fate of chemicals.

[10]  M. Zazzi,et al.  Antiretroviral resistance mutations in human immunodeficiency virus type 1 reverse transcriptase and protease from paired cerebrospinal fluid and plasma samples. , 2000, The Journal of infectious diseases.

[11]  R. Farinotti,et al.  Kinetics of Antiviral Activity and Intracellular Pharmacokinetics of Human Immunodeficiency Virus Type 1 Protease Inhibitors in Tissue Culture , 1999, Antimicrobial Agents and Chemotherapy.

[12]  R. Gieschke,et al.  Relationships Between Exposure to Saquinavir Monotherapy and Antiviral Response in HIV-Positive Patients , 1999, Clinical pharmacokinetics.

[13]  A. Perelson,et al.  Quantifying residual HIV-1 replication in patients receiving combination antiretroviral therapy. , 1999, The New England journal of medicine.

[14]  P. Kissinger,et al.  Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. , 1998, The New England journal of medicine.

[15]  G. Satten,et al.  Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. , 1998, The New England journal of medicine.

[16]  C. Koenig,et al.  Isolation of intact organelles by differential centrifugation of digitonin-treated hepatocytes using a table Eppendorf centrifuge. , 1998, Analytical biochemistry.

[17]  D. Roden,et al.  The drug transporter P-glycoprotein limits oral absorption and brain entry of HIV-1 protease inhibitors. , 1998, The Journal of clinical investigation.

[18]  J. Sommadossi,et al.  Effect of nucleoside analogs on neurite regeneration and mitochondrial DNA synthesis in PC-12 cells. , 1997, The Journal of pharmacology and experimental therapeutics.

[19]  Bradley Efron,et al.  The Effect of High-Dose Saquinavir on Viral Load and CD4+ T-Cell Counts in HIV-Infected Patients , 1996, Annals of Internal Medicine.

[20]  Broder,et al.  Phosphorylation of 3'-azido-3'-deoxythymidine and selective interaction of the 5'-triphosphate with human immunodeficiency virus reverse transcriptase. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[21]  Oliver H. Lowry,et al.  Protein measurement with the Folin phenol reagent. , 1951, The Journal of biological chemistry.

[22]  S. Khoo,et al.  Effect of alpha1-acid glycoprotein on the intracellular accumulation of the HIV protease inhibitors saquinavir, ritonavir and indinavir in vitro. , 2001, British journal of clinical pharmacology.

[23]  S. Khoo,et al.  Therapeutic drug monitoring as a tool in treating HIV infection. , 2001, AIDS.