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Antimicrobial Agents and Chemotherapy, October 2002, p. 3228-3235, Vol. 46, No. 10
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.10.3228-3235.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Intracellular Accumulation of Human Immunodeficiency Virus Protease Inhibitors

Saye H. Khoo,1 Patrick G. Hoggard,1* Ian Williams,2 E. Rhiannon Meaden,1 Philippa Newton,2 Edmund G. Wilkins,3 Alan Smith,2 John F. Tjia,1 Judy Lloyd,1 Kevin Jones,1 Nick Beeching,4 Peter Carey,5 Barry Peters,6 and David J. Back1

Department of Pharmacology & Therapeutics, University of Liverpool,1 Department of Infectious Diseases, University Hospital Aintree,4 Department of Genitourinary Medicine, Royal Liverpool University Hospital, Liverpool,5 Department of Sexually Transmitted Diseases, Royal Free and University College Medical School, University College,2 Department of Genitourinary Medicine, St. Thomas' Hospital, London,6 Department of Infectious Diseases, North Manchester General Hospital, Manchester, United Kingdom3

Received 22 February 2002/ Returned for modification 30 May 2002/ Accepted 15 July 2002

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.

* Corresponding author. Mailing address: Department of Pharmacology & Therapeutics, University of Liverpool, Block H, First Floor, 70 Pembroke Pl., Liverpool L69 3GF, United Kingdom. Phone: 44 151 794 5919. Fax: 44 151 794 5656. E-mail: patrick{at}liv.ac.uk.

Antimicrobial Agents and Chemotherapy, October 2002, p. 3228-3235, Vol. 46, No. 10
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.10.3228-3235.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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