Valaciclovir (Valtrex), the L-valyl ester of acyclovir, is undergoing clinical development for the treatment and suppression of herpesviral diseases. The absolute bioavailability of acyclovir from valaciclovir and the metabolic disposition of valaciclovir were investigated with healthy volunteers in two separate studies. In a randomized, crossover study, 12 fasting healthy volunteers each received 1,000 mg of oral valaciclovir and a 1-h intravenous infusion of 350 mg of acyclovir. The mean absolute bioavailability of acyclovir was 54.2%, a value three to five times that obtained previously with oral acyclovir. A similar estimate of 51.3% was made from urinary recovery of acyclovir. In the second study, four fasting volunteers received a single oral dose of 1,000 mg of [ 14 C]valaciclovir. The majority of plasma radioactivity was accounted for by acyclovir, with very low plasma valaciclovir concentrations (mean maximum concentration of drug in plasma ‫؍‬ 0.19 M), which were undetectable after 3 h postdose. By 168 h, more than 90% of the administered radioactive dose was recovered, with approximately 46% in urine and 47% in feces. More than 99% of the radioactivity recovered in urine corresponded to acyclovir and its known metabolites, 9-(carboxymethoxymethyl)guanine and 8-hydroxy-9-[(2-hydroxyethoxy)methyl]guanine, with valaciclovir accounting for less than 0.5% of the dose. Acyclovir, but no valaciclovir, was detected in fecal samples. These studies show that after oral administration to humans, valaciclovir is rapidly and virtually completely converted to acyclovir to provide a high level of acyclovir bioavailability in comparison with that following oral administration of acyclovir. The plasma acyclovir exposure obtained following oral administration of valaciclovir is similar to that achieved with doses of intravenous acyclovir, which are effective in the treatment and suppression of the less susceptible herpesviral diseases.

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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)

The primary pathophysiological event in sickling is the intracellular polymerization of deoxygenated haemoglobin S. Tucaresol (589C80;4[2-formyl-3-hydroxyphenoxymethyl] benzoic acid), a substituted benzaldehyde, was designed to interact with haemoglobin to increase oxygen affinity and has been shown to inhibit sickling in vitro. We administered tucaresol to sickle cell patients in the steady state to examine the anti-sickling effect in vivo. Oral doses of tucaresol or placebo were given to nine stable sickle cell patients (aged 17-39 years; tucaresol, six; placebo, three) for 10 d. The first two patients on tucaresol were scheduled to receive a loading dose of 800 mg or 1200 mg (depending on bodyweight) for the first 4 d, followed by maintenance doses of 200 or 300 mg for the next 6 d. Due to concerns over the sharp rise in haematocrit in one patient, subsequent cohorts received 300 mg tucaresol daily throughout the dosing period. The oxygen affinity of haemoglobin S was increased in all patients receiving tucaresol, with between 10% and 24% of the haemoglobin modified, dependent on dose. In all patients on tucaresol, haemolysis was reduced with rises in haemoglobin of 0.9- 3.7 g/dl (mean 2.2 g/dl), falls in lactate dehydrogenase of 16-52%, and a halving of the irreversibly sickled cell counts. These effects were apparent within a few days and persisted for 1-2 weeks following discontinuation of the drug. Three of the six patients on tucaresol developed fever and cervical lymphadenopathy, with onset between days 7 and 11 from start of drug. Further evaluation of the tolerability and efficacy of tucaresol in sickle cell patients is necessary.

1 311C90 is a novel and selective agonist at 5-HTID receptors, with central and peripheral actions, currently in development for the acute oral treatment of migraine. 2 The pharmacokinetic and tolerability profiles of single oral doses from 1-50 mg 311C90 were investigated in 12 healthy male volunteers in a double-blind, placebo-controlled, dose-escalating study. 3 311C90 was well tolerated with most adverse experiences of mild and transient nature. 4 Absorption was rapid with dose-independent kinetics. Median t, , , was 2-4 h although 5 0 4 5 % of eventual C, , , was attained within 1 h. The tli2 was 2.5-3 h with a high apparent plasma clearance (CL/F> 2000 ml min-) and apparent volume of distribution ( V J F ) of 400-500 1. 5 Three metabolites were detected in plasma and urine, one of which, the N-desmethyl metabolite, has 5-HTID agonist activity. 6 311C90 showed no clinically significant effects on blood pressure, heart rate, ECG or laboratory variables at any dose and demonstrated a tolerability and pharmacokinetic profile compatible with an acute oral migraine treatment.