Intracellular Accumulation of Human Immunodeficiency Virus Protease Inhibitors

Overview

Journal Antimicrob Agents Chemother

Publisher American Society for Microbiology

Specialty Pharmacology

Date 2002 Sep 18

PMID 12234849

Citations 22

Authors

Saye H Khoo

Patrick G Hoggard

Ian Williams

E Rhiannon Meaden

Philippa Newton

Edmund G Wilkins

Alan Smith

John F Tjia

Judy Lloyd

Kevin Jones

Nick Beeching

Peter Carey

Barry Peters

David J Back

Affiliations

Soon will be listed here.

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.

Citing Articles

In-vitro and in-vivo assessment of nirmatrelvir penetration into CSF, central nervous system cells, tissues, and peripheral blood mononuclear cells.

Avedissian S, Malik J, Podany A, Neely M, Rhodes N, Scarsi K Sci Rep. 2024; 14(1):10709.

PMID: 38729980 PMC: 11087525. DOI: 10.1038/s41598-024-60935-5.

Quantitation of methotrexate polyglutamates in human whole blood, erythrocytes and leukocytes collected via venepuncture and volumetric absorptive micro-sampling: a green LC-MS/MS-based method.

Daraghmeh D, Moghaddami M, Bobrovskaya L, Proudman S, Wiese M Anal Bioanal Chem. 2022; 414(20):6029-6046.

PMID: 35796782 PMC: 9314280. DOI: 10.1007/s00216-022-04186-1.

The Effect of Rifampicin on Darunavir, Ritonavir, and Dolutegravir Exposure within Peripheral Blood Mononuclear Cells: a Dose Escalation Study.

De Nicolo A, Calcagno A, Motta I, De Vivo E, DAvolio A, Di Perri G Antimicrob Agents Chemother. 2022; 66(6):e0013622.

PMID: 35583344 PMC: 9211429. DOI: 10.1128/aac.00136-22.

Interactions of HIV and Antiretroviral Therapy With Neutrophils and Platelets.

Madzime M, Rossouw T, Theron A, Anderson R, Steel H Front Immunol. 2021; 12:634386.

PMID: 33777022 PMC: 7994251. DOI: 10.3389/fimmu.2021.634386.

Validation of a UHPLC-MS/MS Method to Quantify Twelve Antiretroviral Drugs within Peripheral Blood Mononuclear Cells from People Living with HIV.

De Nicolo A, Ianniello A, Ferrara M, Avataneo V, Cusato J, Antonucci M Pharmaceuticals (Basel). 2020; 14(1).

PMID: 33375547 PMC: 7824452. DOI: 10.3390/ph14010012.

References

van Praag R, Repping S, de Vries J, Lange J, Hoetelmans R, Prins J . Pharmacokinetic profiles of nevirapine and indinavir in various fractions of seminal plasma. Antimicrob Agents Chemother. 2001; 45(10):2902-7. PMC: 90750. DOI: 10.1128/AAC.45.10.2902-2907.2001. View

Jones K, Bray P, Khoo S, Davey R, Meaden E, Ward S . P-Glycoprotein and transporter MRP1 reduce HIV protease inhibitor uptake in CD4 cells: potential for accelerated viral drug resistance?. AIDS. 2001; 15(11):1353-8. DOI: 10.1097/00002030-200107270-00004. View

van Heeswijk R, Stuart J, Burger D, Beijnen J, Borleffs J, Hoetelmans R . Long-term suppression of viral replication despite low plasma saquinavir concentrations in the CHEESE Study. Br J Clin Pharmacol. 2002; 53(2):211-2. PMC: 1874293. DOI: 10.1046/j.1365-2125.2002.01530.x. View

Furman P, Fyfe J, St Clair M, Weinhold K, Rideout J, Freeman G . Phosphorylation of 3'-azido-3'-deoxythymidine and selective interaction of the 5'-triphosphate with human immunodeficiency virus reverse transcriptase. Proc Natl Acad Sci U S A. 1986; 83(21):8333-7. PMC: 386922. DOI: 10.1073/pnas.83.21.8333. View

Schapiro J, Winters M, Stewart F, Efron B, Norris J, Kozal M . The effect of high-dose saquinavir on viral load and CD4+ T-cell counts in HIV-infected patients. Ann Intern Med. 1996; 124(12):1039-50. DOI: 10.7326/0003-4819-124-12-199606150-00003. View

Cui L, Locatelli L, Xie M, Sommadossi J . Effect of nucleoside analogs on neurite regeneration and mitochondrial DNA synthesis in PC-12 cells. J Pharmacol Exp Ther. 1997; 280(3):1228-34. View

Kim R, Fromm M, Wandel C, Leake B, Wood A, Roden D . The drug transporter P-glycoprotein limits oral absorption and brain entry of HIV-1 protease inhibitors. J Clin Invest. 1998; 101(2):289-94. PMC: 508566. DOI: 10.1172/JCI1269. View

Bronfman M, Loyola G, Koenig C . Isolation of intact organelles by differential centrifugation of digitonin-treated hepatocytes using a table Eppendorf centrifuge. Anal Biochem. 1998; 255(2):252-6. DOI: 10.1006/abio.1997.2453. View

Palella Jr F, Delaney K, Moorman A, Loveless M, Fuhrer J, Satten G . Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med. 1998; 338(13):853-60. DOI: 10.1056/NEJM199803263381301. View

10.

Zhang L, Ramratnam B, Tenner-Racz K, He Y, Vesanen M, Lewin S . Quantifying residual HIV-1 replication in patients receiving combination antiretroviral therapy. N Engl J Med. 1999; 340(21):1605-13. DOI: 10.1056/NEJM199905273402101. View

11.

Gieschke R, Fotteler B, Buss N, Steimer J . Relationships between exposure to saquinavir monotherapy and antiviral response in HIV-positive patients. Clin Pharmacokinet. 1999; 37(1):75-86. DOI: 10.2165/00003088-199937010-00005. View

12.

LOWRY O, ROSEBROUGH N, FARR A, RANDALL R . Protein measurement with the Folin phenol reagent. J Biol Chem. 1951; 193(1):265-75. View

13.

Nascimbeni M, Lamotte C, Peytavin G, Farinotti R, Clavel F . Kinetics of antiviral activity and intracellular pharmacokinetics of human immunodeficiency virus type 1 protease inhibitors in tissue culture. Antimicrob Agents Chemother. 1999; 43(11):2629-34. PMC: 89535. DOI: 10.1128/AAC.43.11.2629. View

14.

Venturi G, Catucci M, Romano L, Corsi P, Leoncini F, Valensin P . Antiretroviral resistance mutations in human immunodeficiency virus type 1 reverse transcriptase and protease from paired cerebrospinal fluid and plasma samples. J Infect Dis. 2000; 181(2):740-5. DOI: 10.1086/315249. View

15.

Choo E, Leake B, Wandel C, Imamura H, Wood A, Wilkinson G . Pharmacological inhibition of P-glycoprotein transport enhances the distribution of HIV-1 protease inhibitors into brain and testes. Drug Metab Dispos. 2000; 28(6):655-60. View

16.

Gupta P, Leroux C, Patterson B, Kingsley L, Rinaldo C, Ding M . Human immunodeficiency virus type 1 shedding pattern in semen correlates with the compartmentalization of viral Quasi species between blood and semen. J Infect Dis. 2000; 182(1):79-87. DOI: 10.1086/315644. View

17.

Kakuda T, Page L, Anderson P, Henry K, Schacker T, Rhame F . Pharmacological basis for concentration-controlled therapy with zidovudine, lamivudine, and indinavir. Antimicrob Agents Chemother. 2000; 45(1):236-42. PMC: 90267. DOI: 10.1128/AAC.45.1.236-242.2001. View

18.

Jones K, Hoggard P, Khoo S, Maher B, Back D . Effect of alpha1-acid glycoprotein on the intracellular accumulation of the HIV protease inhibitors saquinavir, ritonavir and indinavir in vitro. Br J Clin Pharmacol. 2001; 51(1):99-102. PMC: 2014422. DOI: 10.1046/j.1365-2125.2001.01324.x. View

19.

Taylor S, Pereira A . Antiretroviral drug concentrations in semen of HIV-1 infected men. Sex Transm Infect. 2001; 77(1):4-11. PMC: 1758331. DOI: 10.1136/sti.77.1.4. View

20.

Huisman M, Smit J, Wiltshire H, Hoetelmans R, Beijnen J, Schinkel A . P-glycoprotein limits oral availability, brain, and fetal penetration of saquinavir even with high doses of ritonavir. Mol Pharmacol. 2001; 59(4):806-13. DOI: 10.1124/mol.59.4.806. View