title: Comparison of pharmacokinetic and metabolic profiling among gossypol, apogossypol and apogossypol hexaacetate.
abstract: OBJECTIVE
  To characterize the stability, pharmacokinetics and metabolism of analogs of gossypol, apogossypol and apogossypol hexaacetate to provide a basis for comparison.
  
  
  METHODS
  Gossypol, apogossypol and apogossypol hexaacetate were incubated in plasma or liver microsomes from various species, or administered to mice, respectively, from which the stability, metabolism and pharmacokinetic profiles of these analogs were quantitatively determined using a liquid chromatography-mass spectrometry (LC/MS/MS) method.
  
  
  RESULTS
  In various species of plasma, apogossypol and gossypol exhibited similar stability, while 20-40% of apogossypol hexaacetate was converted into apogossypol with concurrent formation of the corresponding di-, tri-, tetra-, and penta-acetates of apogossypol. (+/-)-Gossypol and (-)-gossypol showed comparable pharmacokinetic profile and oral bioavailability (12.2-17.6%) with some variations of clearance and V (ss) following oral and intravenous administration to mice. At the same molar dose, apogossypol showed delayed T (max)(1 h), a slower clearance rate and less distribution after administration to mice. Mono- and di-glucuronide conjugates of apogossypol were readily observed in mouse plasma following administration. Apogossypol formulated in sesame oil appeared to possess larger AUC and thus higher oral bioavailability than that formulated in cremophor EL:ethanol:saline. In contrast, intravenous apogossypol hexaacetate exhibited highest clearance rate partially due to its conversion into apogossypol. Concomitant with disappearance of apogossypol hexaacetate (iv), apogossypol converted from apogossypol hexaacetate was quantitatively detected, and accounted for approximately 30% of total plasma apogossypol hexaacetate. Oral apogossypol hexaacetate showed no bioavailability with little apogossypol occurring in the plasma. In human and mouse liver microsomes, glucuronide conjugates of apogossypol and its acetates were readily identified with the exception of gossypol glucuronidation. Apogossypol appeared more stable in human and mouse liver microsomal preparations than gossypol and apogossypol hexaacetate.
  
  
  CONCLUSIONS
  Apogossypol and gossypol show similar oral and intravenous pharmacokinetic profiles and in vitro stability although apogossypol appears to have a slower clearance rate, larger AUC, and better microsomal stability. Apogossypol hexaacetate converts to apogossypol in both in vitro and in vivo settings and lacks any quantifiable oral bioavailability.
authors.affiliation: National Cancer Institute, Rm 8042, 6130 Executive Blvd., Rockville, MD 20852, USA. jiale@mail.nih.gov
authors.forename: Lee
authors.initials: L
authors.lastname: Jia
authors.forename: Lori C
authors.initials: LC
authors.lastname: Coward
authors.forename: Corenna D
authors.initials: CD
authors.lastname: Kerstner-Wood
authors.forename: Ronda L
authors.initials: RL
authors.lastname: Cork
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Gorman
authors.forename: Patricia E
authors.initials: PE
authors.lastname: Noker
authors.forename: Shinichi
authors.initials: S
authors.lastname: Kitada
authors.forename: Marrizio
authors.initials: M
authors.lastname: Pellecchia
authors.forename: John C
authors.initials: JC
authors.lastname: Reed
mesh_terms: D000085:Acetates / Q000493:pharmacokinetics*; D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D002853:Chromatography, Liquid; D003272:Contraceptive Agents, Male / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004285:Dogs; D004337:Drug Carriers; D004355:Drug Stability; D003368:Gossypium / Q000737:chemistry*; D006072:Gossypol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects; D051381:Rats; D013045:Species Specificity; D053719:Tandem Mass Spectrometry; D014018:Tissue Distribution
chemical_list: D000085:Acetates; D003272:Contraceptive Agents, Male; D004337:Drug Carriers; C492806:apogossypol; C524972:apogossypol hexaacetate; D006072:Gossypol