6MNA, the active metabolite of the nonacidic antiinflammatory drug nabumetone, was investigated using intravenous administration for effects on (1) carrageenan paw edema and gastric irritancy compared with either oral nabumetone or both oral and intravenous indomethacin when given acutely and (2) gastrointestinal irritancy when given in repeat dosing studies. Oral doses of nabumetone or intravenous 6MNA produced effective antiinflammatory activity together with significant inhibition of paw exudate PGE2. Antiinflammatory oral doses of nabumetone or intravenous 6MNA produced minimal effects on gastric 6-keto PGF1 alpha production with an absence of gastric damage, in contrast with indomethacin. In repeat dose studies, 6MNA failed to induce gastrointestinal damage even at doses where general toxicity was evident. These results show that in the rat, 6MNA is an effective antiinflammatory drug but even in very high intravenous doses does not have the propensity to induce gastrointestinal damage.

Appropriate dosage selection is a key element in the design of toxicology studies and, hence, is the first step in the process of evaluating the safety of a new chemical or pharmaceutical agent. This demands careful consideration of exposure to the drug or chemical under investigation in relation to the pharmacological or toxicological effects it evokes in an experimental animal. Toxicokinetic data provide this perspective, but they should not be considered exclusively of other data which reflect the specific activity, potency, or metabolism of the drug or chemical in each individual test species. It is equally inappropriate to base dosage selection in toxicology studies exclusively on functional or morphological endpoints that cause effects outside the range which can be accommodated by homeostatic mechanisms and repair processes. Finally, extrapolation of toxicokinetic data across species lines can lead to serious miscalculations with respect to both dosage selection and the process of risk assessment. In each case, decisions should be based on the integration of toxicokinetic data with other measures and endpoints of biological and toxicological effect.

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