title: 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.
authors.affiliation: Department of Pharmacology & Therapeutics, University of Liverpool, United Kingdom.
authors.forename: Saye H
authors.initials: SH
authors.lastname: Khoo
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Hoggard
authors.forename: Ian
authors.initials: I
authors.lastname: Williams
authors.forename: E Rhiannon
authors.initials: ER
authors.lastname: Meaden
authors.forename: Philippa
authors.initials: P
authors.lastname: Newton
authors.forename: Edmund G
authors.initials: EG
authors.lastname: Wilkins
authors.forename: Alan
authors.initials: A
authors.lastname: Smith
authors.forename: John F
authors.initials: JF
authors.lastname: Tjia
authors.forename: Judy
authors.initials: J
authors.lastname: Lloyd
authors.forename: Kevin
authors.initials: K
authors.lastname: Jones
authors.forename: Nick
authors.initials: N
authors.lastname: Beeching
authors.forename: Peter
authors.initials: P
authors.lastname: Carey
authors.forename: Barry
authors.initials: B
authors.lastname: Peters
authors.forename: David J
authors.initials: DJ
authors.lastname: Back
mesh_terms: D000293:Adolescent; D000328:Adult; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000378:metabolism* / Q000627:therapeutic use; D006801:Humans; D019469:Indinavir / Q000008:administration & dosage / Q000378:metabolism* / Q000627:therapeutic use; D007963:Leukocytes, Mononuclear / Q000378:metabolism / Q000821:virology; D008297:Male; D008875:Middle Aged; D019438:Ritonavir / Q000008:administration & dosage / Q000378:metabolism* / Q000627:therapeutic use; D019258:Saquinavir / Q000008:administration & dosage / Q000378:metabolism* / Q000627:therapeutic use; D013347:Subcellular Fractions / Q000378:metabolism; D020298:U937 Cells / Q000378:metabolism / Q000821:virology
chemical_list: D017320:HIV Protease Inhibitors; D019469:Indinavir; D019258:Saquinavir; D019438:Ritonavir