John M. Strong

Clinical pharmacology of 5-iodo-2'-deoxyuridine and 5-iodouracil and endogenous pyrimidine modulation.

We describe the clinical pharmacology and metabolism of 5‐iodo‐2′‐deoxyuridine (IdUrd) during and after a 12‐hour infusion. The kinetics of IdUrd were linear between 250 and 1200 mg/m2. The plasma IdUrd concentration reached steady state in <1 hour. Total body clearance of IdUrd was 750 ml/min/ m2 and the disappearance t½ at the end of the infusion was <5 minutes. The primary metabolite, 5‐iodouracil (IUra), did not reach steady state during the infusion. At the end of the 1200 mg/m2 infusion, the maximum plasma IUra concentration was 100 µmol/L, or about 10 times the simultaneous IdUrd plasma concentration. During the infusion there was at least a fifty‐ to 100‐fold increase in uracil and thymine plasma concentrations. After the infusion, IUra disappearance from plasma was nonlinear, with an apparent Michaelis constant of 30 µmol/L. Plasma uracil and thymine levels slowly decreased after the IdUrd infusion until IUra fell to <30 µmol/L. There was subsequently a parallel and more rapid decrease in the plasma concentrations of uracil and thymine. Uridine, 2′‐deoxyuridine, and thymidine plasma levels did not change significantly as a result of IdUrd therapy. These changes in endogenous pyrimidine pools are consistent with competitive inhibition of dihydrouracil dehydrogenase by IUra. An in vitro human bone marrow assay was used to determine the relative toxicity of IdUrd and IUra. Although exposure to IUra was tenfold higher than that to IdUrd, IdUrd was at least 100 times more cytotoxic to marrow cells.

Plasma levels of methsuximide and N‐desmethylmethsuximide during methsuximide therapy

The plasma concentration of N-desmethylmethsuximide in patients receiving chronic methsuximide therapy averages about 700 times the concentration of the parent drug. Both compounds were measured simultaneously by quadrupole mass fragmentography in the plasma of 17 patients receiving methsuximide for various types of epilepsy. Because methsuximide is only slightly more effective than N-desmethylmethsuximide in anticonvulsant tests on laboratory animals, it is likely that Ndesmethylmethsuximide is primarily responsible for seizure control in these patients. Although more study is needed to define the precise range of therapeutically effective plasma concentrations, plasma levels of N-desmethylmethsuximide below 10 mcg per milliliter appear to be ineffective while those above 40 mcg per milliliter are toxic.

Reactivity of atropaldehyde, a felbamate metabolite in human liver tissue in vitro

Antiepileptic therapy with a broad spectrum drug felbamate (FBM) has been limited due to reports of hepatotoxicity and aplastic anemia associated with its use. It was proposed that a bioactivation of FBM leading to formation of alpha,beta-unsaturated aldehyde, atropaldehyde (ATPAL) could be responsible for toxicities associated with the parent drug. Other members of this class of compounds, acrolein and 4-hydroxynonenal (HNE), are known for their reactivity and toxicity. It has been proposed that the bioactivation of FBM to ATPAL proceeds though a more stable cyclized product, 4-hydroxy-5-phenyltetrahydro-1,3-oxazin-2-one (CCMF) whose formation has been shown recently. Aldehyde dehydrogenase (ALDH) and glutathione transferase (GST) are detoxifying enzymes and targets for reactive aldehydes. This study examined effects of ATPAL and its precursor, CCMF on ALDH, GST and cell viability in liver, the target tissue for its metabolism and toxicity. A known toxin, HNE, which is also a substrate for ALDH and GST, was used for comparison. Interspecies difference in metabolism of FBM is well documented, therefore, human tissue was deemed most relevant and used for these studies. ATPAL inhibited ALDH and GST activities and led to a loss of hepatocyte viability. Several fold greater concentrations of CCMF were necessary to demonstrate a similar degree of ALDH inhibition or cytotoxicity as observed with ATPAL. This is consistent with CCMF requiring prior conversion to the more proximate toxin, ATPAL. GSH was shown to protect against ALDH inhibition by ATPAL. In this context, ALDH and GST are detoxifying pathways and their inhibition would lead to an accumulation of reactive species from FBM metabolism and/or metabolism of other endogenous or exogenous compounds and predisposing to or causing toxicity. Therefore, mechanisms of reactive aldehydes toxicity could include direct interaction with critical cellular macromolecules or indirect interference with cellular detoxification mechanisms.