title: Assessment of effective renal plasma flow, enzymuria, and cytokine release in healthy volunteers receiving a single dose of amphotericin B desoxycholate.
abstract: The present study assessed potential subclinical markers of amphotericin B (AmB)-related nephrotoxicity and infusion-related reactions (IRR). Subjects were pretreated with diphenhydramine and acetaminophen and received a 500-ml bolus infusion of 0.9% sodium chloride prior to each effective renal plasma flow (ERPF) assessment. ERPF was measured before and after administration of a single 0.25-mg/kg intravenous AmB dose using technetium-99m mercaptoacetyltriglycine. Blood was collected before and 3 h after AmB infusion for tumor necrosis factor alpha (TNF-alpha) and interleukin-1beta (IL-1beta) plasma concentrations. Overnight 12-h urine collections were performed before administration of AmB and for 2 nights after administration of AmB and analyzed for alpha and pi glutathione-S-transferases (GSTalpha and GSTpi, respectively) and N-acetyl-beta-d-glucosaminidase (NAG). Six men and six women with mean +/- standard deviation (SD) ages of 24.8 +/- 5.3 and 28.0 +/- 8.5 years, respectively, were studied. Baseline serum creatinine values were within the normal range and were unaltered after administration of AmB. The mean +/- SD decrease in ERPF after administration of AmB was significant (P < 0.05) in males (15.7 +/- 8.1%) but not females (9.5 +/- 14.0%). The GSTpi and GSTalpha indices increased significantly (P < 0.05) by two to fourfold and returned to baseline in males but were unaltered in females. NAG indices were unaffected by AmB. Six patients experienced an IRR that was associated with increased TNF-alpha (P < 0.05) but not IL-1beta (P = 0.09). These results suggest a potential sex-related difference in AmB-induced nephrotoxicity and provide a rationale for use of ERPF, urine GST, and TNF-alpha as subclinical markers of polyene-induced toxicity.
authors.affiliation: College of Pharmacy, MSC09 5360, University of New Mexico, Albuquerque, NM 87131-0001, USA. apai@salud.unm.edu.
authors.forename: Manjunath P
authors.initials: MP
authors.lastname: Pai
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Norenberg
authors.forename: Robert A
authors.initials: RA
authors.lastname: Telepak
authors.forename: David S
authors.initials: DS
authors.lastname: Sidney
authors.forename: Shu
authors.initials: S
authors.lastname: Yang
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000666:Amphotericin B / Q000009:adverse effects / Q000494:pharmacology*; D000935:Antifungal Agents / Q000009:adverse effects / Q000494:pharmacology*; D003404:Creatinine / Q000097:blood; D016207:Cytokines / Q000378:metabolism*; D003840:Deoxycholic Acid / Q000009:adverse effects / Q000494:pharmacology*; D004338:Drug Combinations; D004798:Enzymes / Q000652:urine*; D005260:Female; D006801:Humans; D007375:Interleukin-1 / Q000096:biosynthesis; D007677:Kidney Function Tests; D008297:Male; D008875:Middle Aged; D017595:Renal Plasma Flow / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D000935:Antifungal Agents; D016207:Cytokines; D004338:Drug Combinations; D004798:Enzymes; D007375:Interleukin-1; D014409:Tumor Necrosis Factor-alpha; D003840:Deoxycholic Acid; D000666:Amphotericin B; C059765:amphotericin B, deoxycholate drug combination; D003404:Creatinine