title: Feasibility of radiolabeled small molecule permeability as a quantitative measure of microbicide candidate toxicity.
abstract: OBJECTIVE
  To determine the feasibility of using quantitative changes in vaginal permeability to small molecules as a measure of candidate microbicide toxicity.
  
  
  METHODS
  Controlled, open-labeled, prospective study. Seven healthy women received a single vaginal dose of hydroxyethylcellulose gel (HEC), nonoxynol-9 (N-9) or K-Y Jelly. Each gel was radiolabeled with a small molecule ((99m)Tc-DTPA) followed by 12-h blood and urine collection. Pharmacokinetic (PK) parameters of (99m)Tc-DTPA were calculated to compare the impact of each gel on vaginal permeability. Each woman served as her own control. The Friedman test with post hoc Wilcoxon test was used to detect differences among the gels.
  
  
  RESULTS
  Vaginal permeability of (99m)Tc-DTPA was highest for the N-9 radiolabel. N-9 plasma area under the concentration curve was 2.7-fold higher (p=.04), and peak concentration was threefold higher (p=.04) compared to HEC. There were no significant PK parameter differences between HEC and K-Y Jelly or between N-9 and K-Y Jelly. Cumulative dose-adjusted median (interquartile range) 12-h timed urine gamma activity was 66.70 × 10(-4)μCi (27.90-152.00) following HEC dosing, 103.00 × 10(-4)μCi (98.20-684.00) following N-9 gel dosing and 20.30 × 10(-4)μCi (11.10-55.90) following K-Y gel dosing. The differences between urine HEC and K-Y Jelly (p=.047) and between N-9 and K-Y Jelly (p=.016) were statistically significant.
  
  
  CONCLUSIONS
  It is feasible to measure differences in vaginal permeability among vaginal gels using a radiolabeled small molecule, though there are permeability differences that require a nuanced understanding of gel composition to interpret the results.
  
  
  CONCLUSIONS
  Establishing the safety of both vehicle and active pharmaceutical ingredient is an essential task in microbicide development, to be determined as soon as possible. This study suggests that a combination of microbicide toxicity assessments, that is, cervicovaginal permeability, inspection and histopathology, may need to be studied simultaneously.
authors.affiliation: Johns Hopkins University School of Medicine, Department of Gynecology & Obstetrics; Johns Hopkins University School of Medicine Division of Clinical Pharmacology, Department of Medicine. Electronic address: colemanj@jhmi.edu.
authors.forename: Jenell S
authors.initials: JS
authors.lastname: Coleman
authors.affiliation: Johns Hopkins University School of Medicine Division of Clinical Pharmacology, Department of Medicine.
authors.forename: Edward
authors.initials: E
authors.lastname: Fuchs
authors.affiliation: Johns Hopkins University School of Medicine Division of Clinical Pharmacology, Department of Medicine.
authors.forename: Wutyi S
authors.initials: WS
authors.lastname: Aung
authors.affiliation: Johns Hopkins University School of Medicine Division of Clinical Pharmacology, Department of Medicine; Johns Hopkins University School of Medicine, Department of Pathology.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Marzinke
authors.affiliation: Johns Hopkins University School of Medicine Division of Clinical Pharmacology, Department of Medicine.
authors.forename: Rahul P
authors.initials: RP
authors.lastname: Bakshi
authors.affiliation: HJF-DAIDS, a Division of The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Contractor to National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services.
authors.forename: Hans M L
authors.initials: HML
authors.lastname: Spiegel
authors.affiliation: Johns Hopkins University School of Medicine, Department of Gynecology & Obstetrics; Johns Hopkins University School of Medicine Division of Clinical Pharmacology, Department of Medicine.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Robinson
authors.affiliation: Johns Hopkins University School of Medicine Division of Clinical Pharmacology, Department of Medicine.
authors.forename: Craig W
authors.initials: CW
authors.lastname: Hendrix
mesh_terms: D000293:Adolescent; D000328:Adult; D000890:Anti-Infective Agents; D002463:Cell Membrane Permeability; D002482:Cellulose / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D005260:Female; D005782:Gels; D005990:Glycerol / Q000008:administration & dosage / Q000493:pharmacokinetics; D015658:HIV Infections / Q000517:prevention & control; D006801:Humans; D008875:Middle Aged; D017137:Nonoxynol / Q000008:administration & dosage / Q000493:pharmacokinetics; D010710:Phosphates / Q000008:administration & dosage / Q000493:pharmacokinetics; D011409:Propylene Glycols / Q000008:administration & dosage / Q000493:pharmacokinetics; D011446:Prospective Studies; D016284:Technetium Tc 99m Pentetate / Q000493:pharmacokinetics; D014621:Vagina / Q000378:metabolism*; D014622:Vaginal Creams, Foams, and Jellies / Q000737:chemistry / Q000493:pharmacokinetics
chemical_list: D000890:Anti-Infective Agents; D005782:Gels; C042973:K-Y jelly; D010710:Phosphates; D011409:Propylene Glycols; D014622:Vaginal Creams, Foams, and Jellies; D017137:Nonoxynol; D002482:Cellulose; C002283:hydroxyethylcellulose; D005990:Glycerol; D016284:Technetium Tc 99m Pentetate
keywords: HIV; Microbicide; N-9; Permeability; Spermicide