In four experiments, we tested whether perceptual identification is impeded by temporal overlap with another task. The results demonstrate that temporal overlap with an auditory task consistently impaired the identification of the highest digit in a briefly presented and masked array of digits. The impairment was especially pronounced when we emphasized speed on the auditory task, thus counteracting the normal tendency to focus advance preparation on the more challenging visual task. The data also indicate that previous findings of minimal effects oftemporal overlap may have been due to the use of a restricted range of stimulus onset asynchronies. The present results demonstrate the important role of preparatory strategies in overlapping-task performance, and show that perceptual identification is impeded by the overlapping performance of another task.

Summary Etoposide phosphate is a water-soluble prodrug of etoposide. The plasma pharmacokinetics of etoposide following oral administration of etoposide phosphate or oral etoposide were compared. Seventeen patients with solid tumours were enrolled to receive oral etoposide phosphate 125 mg m-2 on days 1-5 every 3 weeks, with escalation to 175 mg m-2 from course 3 when possible. Patients were randomized to receive oral etoposide phosphate or oral etoposide on day 1 of course 1 and the alternative compound on day 1 of course 2.Fifteen patients received two or more courses and were evaluable for pharmacokinetic comparisons. The median AUCinf (area under the concentration vs time curve from zero to infinity) of etoposide was 77.7 mg 1-1 h after etoposide phosphate (95% Cl 61.3-100.5) and 62.0 mg 1-1 h after oral etoposide (95% Cl 52.2-76.9). The difference in favour of etoposide phosphate was borderline significant: median 9.9 mg 1-1 h (95% Cl 0.1-32.8 mg 1-1 h; P = 0.05). However, the inter-patient variability of etoposide AUCinf was not improved (coefficients of variation 42.3% and 48.4%). Etoposide phosphate was undetectable in plasma after oral administration. Toxicities of oral etoposide phosphate were not different from those known for etoposide. In conclusion, oral etoposide phosphate does not offer a clinically relevant benefit over oral etoposide.Keywords: etoposide; etoposide phosphate; oral; pharmacokinetics; toxicity Etoposide, a podophyllotoxin derivative, is incorporated in standard chemotherapy for treatment of small-cell lung cancer (SCLC) and germ cell tumours, as well as in second-line treatment for haematological and many other malignancies . Activity is improved considerably when the dose is divided over several days, and therefore oral administration is attractive (Slevin et al, 1989a). It has been shown that oral etoposide monotherapy, usually with the dose divided over 5 days or longer periods, is an effective treatment in patients with SCLC and refractory malignant lymphomas . In small studies, prolonged oral etoposide treatment showed remarkable activity in relapsed or refractory breast and ovarian cancers (response rates up to 35% and 25% respectively) (Hoskins and Swenerton, 1994;Martin et al, 1994). Patient convenience is an important additional reason for choosing the oral route. However, pharmacokinetic studies have shown that oral etoposide also has disadvantages. Bioavailability is incomplete, probably decreasing with dose, and is reported to be below 50% for doses above 200 mg. Bioavailability shows wide inter-and intra-patient variability (Hande et al, 1993;Harvey et al, 1985;Slevin et al, 1989b). The consequences are considerable risks of underdosing and unpredictable toxicity.The water-soluble prodrug etoposide phosphate was synthesized because use of intravenous etoposide administration is Received 30 September 1996 Revised 19 December 1996 Accepted 20 December 1996 Correspondence to: EGE de Vries, Division of Medical Oncology, Department of Internal Medicine, University Hos...

Summary Etoposide phosphate is a water-soluble prodrug of etoposide. It was expected that this prodrug could be used to overcome the solubility limitations and erratic bioavailability of oral etoposide. To investigate the possibility of prodrug conversion to etoposide within the gastrointestinal lumen, etoposide phosphate was dissolved in water and incubated with human gastric juice or human bile in vitro. Samples were collected during 150 min and analysed for etoposide concentration with high-performance liquid chromatography. Conversion of prodrug to etoposide during incubation with gastric juice was negligible. There was significant conversion during incubation with bile at pH 7-8. The percentage of prodrug converted to etoposide at pH 8 after 60 min was 78 ± 18% (mean ± S.D.) for a 0.1 mg ml-' prodrug solution and 36 ± 26% for 0.5 mg ml-'. At pH 7, after 60 min 22% of prodrug was converted to etoposide when incubated at 0.1 mg ml-' and 10% at 0.5 mg ml-'. No conversion was found after inactivation of alkaline phosphate (AP) by overnight heating of bile at 650C or by the addition of disodium edetate to the bile. In conclusion, because of AP in bile, variable conversion of etoposide phosphate to etoposide can be expected within the intestinal lumen after oral administration. This could have important pharmacokinetic consequences.

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