PHARMACOLOGICAL ATTEMPTS TO IMPROVE THE BIOAVAILABILITY OF ORAL ETOPOSIDE

Etoposide demonstrates incomplete and variable bioavailability after o ral dosing, which may be due to its concentration and pH-dependent sta bility in artificial gastric and intestinal fluids. The use of agents that may influence etoposide stability and, thereby, bioavailability, was investigated in a number of clinical studies. Drugs that influence the rate of gastric emptying, while modulating the time of drug absor ption, did not significantly alter the etoposide area under the concen tration-time curve (AUG) or bioavailability. Specifically, metoclopram ide had little effect on the etoposide absorption profile and did not significantly alter the AUC (AUC with etoposide alone, 68.4 +/- 20.3 m u g ml(-1) h, versus 74.3 +/- 25.9 mu g ml(-1) h with metoclopramide), suggesting that in most patients the drug is already emptied rapidly from the stomach. In contrast, propantheline produced a dramatic effec t on etoposide absorption, delaying the time of maximal concentration t(max) from 1.1 to 3.5 h (P < 0.01), but again without a significant i mprovement in drug AUC or bioavailability across the 24-h study period (AUG with etoposide alone 78.3 +/- 19.1 mu g ml(-1) h, versus 88.1 +/ - 23.6 mu g ml(-1) h with propantheline). The effect of these drugs on the absorption of oral paracetamol, a drug included in the study as a marker of gastric emptying, was exactly the same as that found for et oposide, with no change in AUC being observed after metoclopramide or propantheline administration but a significant delay in t(max) being s een on co-administration with etoposide and propantheline. The co-admi nistration of ethanol or bile salts (agents that significantly improve d the stability of etoposide in artificial intestinal fluid) with oral etoposide similarly had no effect on improving the etoposide AUC or r educing the variability in AUG, suggesting that drug stability in vivo was not affected by these agents. In the third study; the co-administ ration of cimetidine had no effect on the pharmacokinetics of oral or i.v. etoposide, despite the previous observation that etoposide stabil ity was markedly improved at pH 3-5 as compared with pH 1 in artificia l gastric fluid. This series of studies, designed to investigate facto rs that improved etoposide stability in laboratory studies, failed to demonstrate any potentially useful improvement in AUC or bioavailabili ty in the clinical setting.