title: Toxicology and pharmacokinetics of piperaquine in mice.
abstract: Pharmacokinetic and toxicological data for piperaquine (PQ) - a bisquinoline antimalarial drug - are limited, despite strong evidence of clinical efficacy. Our aim was to conduct a detailed toxicological investigation of PQ in Swiss mice. The study comprised three phases: (i) oral PQ phosphate (PQP) at doses ranging from 0 to 600 mg/(kg day) for 5 days. Pathology tests included haematological and biochemical indices, and histopathology of the liver, heart and kidneys. (ii) PQP doses of 0-300 mg/(kg day) for 12 days and pathology tests as described. (iii) Pharmacokinetic parameters determined from mice given 100mg/(kg day) PQP for 5 days. Blood was harvested from mice over 56 days and plasma analysed by HPLC. Mice given low doses of PQ had stable, normal body and organ weights. Weight loss was observed in mice given high doses and was accompanied by increased liver and kidney weights. Principal haematological effects were modest fluctuations in total white cells and neutrophils; biochemical effects were elevated ALT and low albumin in high-dose groups. Liver histopathology revealed minor cytoplasmic and inflammatory effects. PQ treatment did not affect heart muscle but minor renal changes were observed at high doses. Pharmacokinetic parameters were consistent with previous studies: t1/2, CL and V were 16 days, 1.36 L/(h kg) and 756 L/kg, respectively. PQ may cause minor hepatotoxicity and renal tubular cell damage, and adversely affect selected haematological indices, as demonstrated at cumulative doses approximately 50 times those recommended in humans. Significant effects in humans will likely be infrequent and dose-related.
authors.affiliation: School of Pharmacy, Curtin University of Technology, Bentley, Western Australia, Australia. Kevin.Batty@curtin.edu.au <Kevin.Batty@curtin.edu.au>
authors.forename: Kevin T
authors.initials: KT
authors.lastname: Batty
authors.forename: Brioni R
authors.initials: BR
authors.lastname: Moore
authors.forename: Verity
authors.initials: V
authors.lastname: Stirling
authors.forename: Kenneth F
authors.initials: KF
authors.lastname: Ilett
authors.forename: Madhu
authors.initials: M
authors.lastname: Page-Sharp
authors.forename: Keith B
authors.initials: KB
authors.lastname: Shilkin
authors.forename: Ivo
authors.initials: I
authors.lastname: Mueller
authors.forename: Harin A
authors.initials: HA
authors.lastname: Karunajeewa
authors.forename: Timothy M E
authors.initials: TM
authors.lastname: Davis
mesh_terms: D000284:Administration, Oral; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000962:Antimalarials / Q000493:pharmacokinetics* / Q000633:toxicity*; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D005260:Female; D006321:Heart / Q000187:drug effects; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000473:pathology; D051379:Mice; D009206:Myocardium / Q000473:pathology; D009504:Neutrophils / Q000187:drug effects; D009929:Organ Size / Q000187:drug effects; D011804:Quinolines / Q000493:pharmacokinetics* / Q000633:toxicity*; D012709:Serum Albumin / Q000032:analysis; D018675:Toxicity Tests; D010879:Piperazines
chemical_list: D000410:Alanine Transaminase; D000962:Antimalarials; D011804:Quinolines; D012709:Serum Albumin; C034759:piperaquine; D010879:Piperazines