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 ester (FPMH) are completely hydrolyzed during penetration through human and rat skin in vitro to the acid metabolite, fluroxypyr (FP) (). This article presents additional studies to determine the enzyme kinetics (K(m) and V(max)) of this ester hydrolysis, using crude rat whole-skin homogenate. Both FPM and FPMH were extensively metabolized in rat skin homogenates to the acid metabolite, FP. In no instance were any other metabolites detected. FPM was essentially hydrolyzed completely within 1 h. In FPMH incubations, there was still parent ester present after 24 h at all concentrations tested. The kinetics of hydrolysis of the two esters were different: V(max) was approximately 3-fold greater for FPM than FPMH (1400 and 490 micromol FP/min/g of tissue, respectively); however, K(m) values were very similar, 251 and 256 microM, respectively. Preliminary inhibitory studies suggest that FPM and FPMH are hydrolyzed by a carboxylesterase, because this reaction was inhibited by bis-p-nitrophenyl phosphate. Mercuric chloride (an inhibitor of A-esterase and arylesterase) and eserine (a cholinesterase inhibitor) had no inhibitory effect on the hydrolysis of FPM or FPMH. Taken together with the data presented by, it can be concluded that no parent ester will pass through the skin in vivo, only the metabolite, FP. Therefore, first pass metabolism will be complete before these compounds reach the systemic circulation.
Hewitt
P G
PG
Section of Molecular Toxicology, Imperial College School of Medicine, South Kensington, London, United Kingdom. phillip.hewitt@merck.de
Perkins
J
J
Hotchkiss
S A
SA
D000818:Animals; D004950:Esterases / Q000378:metabolism; D006016:Glycolates / Q000737:chemistry / Q000493:pharmacokinetics*; D006540:Herbicides / Q000737:chemistry / Q000493:pharmacokinetics*; D006868:Hydrolysis; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D012867:Skin / Q000201:enzymology / Q000378:metabolism*
D006016:Glycolates; D006540:Herbicides; C078450:fluroxypyr methylheptyl ester; D004950:Esterases