Examination of some factors responsible for a food-induced increase in absorption of atovaquone.
1. Atovaquone is a potent antiprotozoal slowly and irregularly absorbed after administration as tablets to fasting volunteers. A series of studies was performed to investigate the effects of food, bile and formulation on atovaquone absorption. 2. In 18 healthy male volunteers, a high-fat breakfast administered 45 min before 500 mg atovaquone as tablets increased AUC by 3.3-fold (95% CI 2.8-4.0) and Cmax 5.3-fold (4.3-6.6) compared with fasting. 3. The absorption of atovaquone from tablets was examined in 12 healthy male volunteers after an overnight fast, following toast alone, toast with 28 g butter (LOFAT), or toast with 56 g butter (HIFAT). Compared with absorption when fasted, toast had no significant effect but LOFAT increased AUC 3.0-fold (2.1-4.2) and Cmax 3.9-fold (2.6-5.8). HIFAT increased AUC 3.9-fold (2.7-5.5) and Cmax 5.6-fold (3.8-8.4). 4. The absorption of atovaquone was examined in nine healthy fasting male volunteers from tablets, an aqueous suspension, and an oily solution/suspension in miglyol (fractionated coconut oil). Compared with tablets, AUC following the aqueous suspension was increased 1.7-fold (1.0-2.7) and Cmax 2.4-fold (1.7-3.5). Following miglyol, AUC was increased to the same extent but Cmax was only increased 1.8-fold (1.2-2.6). 5. Atovaquone absorption was examined in eight healthy fasting male volunteers following an i.v. infusion of cholecystokinin octapeptide (CCK-OP) which decreased gallbladder volume by 82% (73%-90%) on occasion 1 or saline on occasion 2. AUC(0,12) was increased following CCK-OP by 1.6-fold (1.1-2.4) and Cmax by 1.5-fold (0.98-2.4).(ABSTRACT TRUNCATED AT 250 WORDS)
Rolan
P E
PE
Wellcome Research Laboratories, Beckenham, Kent.
Mercer
A J
AJ
Weatherley
B C
BC
Holdich
T
T
Meire
H
H
Peck
R W
RW
Ridout
G
G
Posner
J
J
D000328:Adult; D053626:Atovaquone; D002851:Chromatography, High Pressure Liquid; D004041:Dietary Fats / Q000008:administration & dosage*; D005215:Fasting; D005502:Food; D006801:Humans; D007262:Infusions, Intravenous; D007408:Intestinal Absorption / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D009285:Naphthoquinones / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D012844:Sincalide / Q000008:administration & dosage / Q000494:pharmacology; D013535:Suspensions; D013607:Tablets
D004041:Dietary Fats; D009285:Naphthoquinones; D013535:Suspensions; D013607:Tablets; D012844:Sincalide; D053626:Atovaquone