Kevin T Batty1, Kenneth F Ilett, Timothy M E Davis. 1. Pharmacology Unit, School of Medicine and Pharmacology, University of Western Australia, Crawley, Western Australia, Australia. Kevin.Batty@curtin.edu.au
Abstract
AIMS: To determine the ratio of alpha : beta anomers and the protein binding of dihydroartemisinin (DHA) in vivo. METHODS: 10-[(3)H]-DHA was synthesized by reduction of artemisinin with sodium boro-[(3)H]-hydride and purified with preparative thin layer chromatography. A solution of (3)H-DHA (2000 ng in 20 micro l) was added to 2 ml whole blood from 15 healthy volunteers and 22 Vietnamese patients with falciparum or vivax malaria. The blood was centrifuged and the plasma stored at -25 degrees C until analysed by HPLC with radiochromatographic detection. Protein-free ultrafiltrate of the plasma was assayed to determine the free fraction of DHA and the in vivo ratio of alpha-DHA : beta-DHA. RESULTS: The DHA fraction unbound (mean +/- SD) was 0.068 +/- 0.032 in Vietnamese patients with falciparum malaria (n = 17), 0.065 +/- 0.009 in Vietnamese patients with vivax malaria (n = 5), 0.117 +/- 0.015 in Vietnamese volunteers (n = 7) and 0.092 +/- 0.020 in Caucasian volunteers (n = 8). The ratios of alpha-DHA : beta-DHA for the four groups were 6.3 +/- 0.9, 6.9 +/- 0.8, 6.9 +/- 0.6 and 5.4 +/- 0.8, respectively. CONCLUSIONS: DHA is approximately 93% protein-bound in patients with malaria infection and there is a preferential existence in vivo of the alpha-DHA anomer. Knowledge of this stereochemistry may be valuable in elucidation of the mechanisms of DHA action and/or toxicity, and in the synthesis of new trioxane antimalarials.
AIMS: To determine the ratio of alpha : beta anomers and the protein binding of dihydroartemisinin (DHA) in vivo. METHODS:10-[(3)H]-DHA was synthesized by reduction of artemisinin with sodium boro-[(3)H]-hydride and purified with preparative thin layer chromatography. A solution of (3)H-DHA (2000 ng in 20 micro l) was added to 2 ml whole blood from 15 healthy volunteers and 22 Vietnamese patients with falciparum or vivax malaria. The blood was centrifuged and the plasma stored at -25 degrees C until analysed by HPLC with radiochromatographic detection. Protein-free ultrafiltrate of the plasma was assayed to determine the free fraction of DHA and the in vivo ratio of alpha-DHA : beta-DHA. RESULTS: The DHA fraction unbound (mean +/- SD) was 0.068 +/- 0.032 in Vietnamese patients with falciparum malaria (n = 17), 0.065 +/- 0.009 in Vietnamese patients with vivax malaria (n = 5), 0.117 +/- 0.015 in Vietnamese volunteers (n = 7) and 0.092 +/- 0.020 in Caucasian volunteers (n = 8). The ratios of alpha-DHA : beta-DHA for the four groups were 6.3 +/- 0.9, 6.9 +/- 0.8, 6.9 +/- 0.6 and 5.4 +/- 0.8, respectively. CONCLUSIONS:DHA is approximately 93% protein-bound in patients with malaria infection and there is a preferential existence in vivo of the alpha-DHA anomer. Knowledge of this stereochemistry may be valuable in elucidation of the mechanisms of DHA action and/or toxicity, and in the synthesis of new trioxane antimalarials.
Authors: T Q Binh; K F Ilett; K T Batty; T M Davis; N C Hung; S M Powell; L T Thu; H V Thien; H L Phuöng; V D Phuong Journal: Br J Clin Pharmacol Date: 2001-06 Impact factor: 4.335
Authors: P Newton; Y Suputtamongkol; P Teja-Isavadharm; S Pukrittayakamee; V Navaratnam; I Bates; N White Journal: Antimicrob Agents Chemother Date: 2000-04 Impact factor: 5.191
Authors: T M Davis; H L Phuong; K F Ilett; N C Hung; K T Batty; V D Phuong; S M Powell; H V Thien; T Q Binh Journal: Antimicrob Agents Chemother Date: 2001-01 Impact factor: 5.191
Authors: Kenneth F Ilett; Brian T Ethell; James L Maggs; Timothy M E Davis; Kevin T Batty; Brian Burchell; Tran Quang Binh; Le Thi Anh Thu; Nguyen Canh Hung; Munir Pirmohamed; B Kevin Park; Geoffrey Edwards Journal: Drug Metab Dispos Date: 2002-09 Impact factor: 3.922
Authors: Timothy M E Davis; Tran Quang Binh; Kenneth F Ilett; Kevin T Batty; Hoang Lan Phuöng; Gregory M Chiswell; Vu Duong Bich Phuong; Cindy Agus Journal: Antimicrob Agents Chemother Date: 2003-01 Impact factor: 5.191
Authors: Kashyap Patel; Kevin T Batty; Brioni R Moore; Peter L Gibbons; Jürgen B Bulitta; Carl M Kirkpatrick Journal: Antimicrob Agents Chemother Date: 2012-11-12 Impact factor: 5.191
Authors: I C E Hendriksen; G Mtove; A Kent; S Gesase; H Reyburn; M M Lemnge; N Lindegardh; N P J Day; L von Seidlein; N J White; A M Dondorp; J Tarning Journal: Clin Pharmacol Ther Date: 2013-02-08 Impact factor: 6.875