Metabolism of fluroxypyr, fluroxypyr methyl ester, and the herbicide fluroxypyr methylheptyl ester. II: In rat skin homogenates

Fluroxypyr methyl ester (FPM) and the herbicide fluroxypyr methylheptyl est er (FPMH) are completely hydrolyzed during penetration through human and ra t skin in vitro to the acid metabolite, fluroxypyr (FP) (Hewitt et al., 200 0). This article presents additional studies to determine the enzyme kineti cs (Km and Vmax) of this ester hydrolysis, using crude rat whole-skin homog enate. Both FPM and FPMH were extensively metabolized in rat skin homogenat es to the acid metabolite, FP. In no instance were any other metabolites de tected. FPM was essentially hydrolyzed completely within 1 h. In FPMH incub ations, there was still parent ester present after 24 h at all concentratio ns tested. The kinetics of hydrolysis of the two esters were different: Vma x was approximately fold greater for FPM than FPMH (1400 and 490 mu mol FP/ min/g of tissue, respectively); however, Km values were very similar, 251 a nd 256 mu M, respectively. Preliminary inhibitory studies suggest that FPM and FPMH are hydrolyzed by a carboxylesterase, because this reaction was in hibited by bis-p-nitrophenyl phosphate. Mercuric chloride (an inhibitor of A-esterase and arylesterase) and eserine (a cholinesterase inhibitor) had n o inhibitory effect on the hydrolysis of FPM or FPMH. Taken together with t he data presented by Hewitt et al. (2000), it can be concluded that no pare nt ester will pass through the skin in vivo, only the metabolite, FP. There fore, first pass metabolism will be complete before these compounds reach t he systemic circulation.