The metabolic fate of pyrethrin I, pyrethrin II, and allethrin*

Bull. Org. mond. Sante} 1971, 44, 347-348 Bull. Wld Hlth Org. The Metabolic Fate of Pyrethrin I, Pyrethrin II, and Allethrin* IZURU YAMAMOTO, MICHAEL ELLIOTT & JOHN E. CASIDA By the administration of radioactively labelled compounds, the metabolic products of pyrethrin I, pyrethrin II, and allethrin in the rat have been identified. This paper describes the structures of the metabolites. On the basis of results obtained with 14C-labelled preparations, allethrin is metabolized in living houseflies and by the housefly mixed-function oxi- dase system by attack at the trans-methyl (major site) and cis-methyl (minor site) groups of the iso- butenyl side chain in the acid moiety, forming, in succession, the corresponding hydroxymethyl, aide- hyde and acid compounds. Hydrolysis or attack on the alcoholic part of the ester apparently does not occur, but trace amounts of unidentified meta- bolites are found. Piperonyl butoxide inhibits hydroxylation of the methyl groups by the mixed- function oxidase system. Living houseflies con- jugate and excrete the hydroxymethyl compounds, probably as glucosides. Pyrethrin I, tetramethrin, and dimethrin are similarly metabolized, in vivo and in vitro, by oxidation of the trans-methyl group. Resistant fly strains metabolize allethrin more rapidly than susceptible strains. Rat liver microsomes metabolize pyrethrin I only when the reaction mixtures are fortified with NADPH, and they produce the same products whether 14C-acid-labelled or 3H-alcohol-labelled pyrethrin I is used, indicating that the metabolites are esters. Thus, there is evidence that the rat liver microsomal system produces pyrethrin-wt-ol, pyrethrin-wt-al, and pyrethrin-wt-oic acid as meta- bolites, but only when a low level of enzyme is used; at high enzyme levels, more polar metabolites are formed. Metabolites of pyrethrin I and pyrethrin II occur in the expired air, urine, and faeces of rats to which these compounds are administered. The oral administration of a single dose of radioactive pyrethrin II ("4C-labelled in the methyl of the methoxy-carbonyl group) and "4C-methanol to male rats produces, respectively, 53 % and 67% * From the Division of Entomology, University of California, Berkeley, Calif., USA. of radioactive expiration products and 24% and 23 % of excretory products in a period of 2 days. The radiolabelled metabolites found in the urine are the same whether the rats are fed 3H-alcohol-labelled or 14C-acid-labelled pyrethrin I. The metabolites found in the urine of rats are also present in the faeces but, in addition, the faeces contain some unmetabolized compound (more of pyrethrin I than of pyrethrin II). In the 100-hour period fol- lowing the administration of tritium-labelled pyre- thrin I or pyrethrin II, rats excrete 65-70% of the tritium, equal amounts being found in the urine and in the faeces. The proportion of metabolites remains about the same for doses that range from 0.1 mg/kg to 400 mg/kg. When repeated doses of radioactive pyrethrin 1, pyrethrin II, and alle- thrin (tritium-labelled in the alcohol moiety) are administered orally to male rats over a 2-day period the urine is found to contain approximately one- fifth or more of the administered radioactivity. The principal metabolite of pyrethrin I in rats is the same as that of pyrethrin II and has a carboxyl group on the isobutenyl group of the acid moiety and a cis-4',5'-dihydroxypent-2'-en-1 '-yl group in the alcohol moiety (metabolite A in the accompanying table). The other metabolites that have been identi- fied are described below. Metabolite B is the trans-2',5'-dihydroxypent- 3 '-en-i'-yl isomer of metabolite A. Metabolite A and metabolite B result from oxidation of the trans-methyl group or hydrolysis of the methoxy- carbonyl group of pyrethrin I or pyrethrin II, respectively; in addition, each pyrethrin suffers attack on the pentadienyl side chain, possibly forming a 4',5'-epoxide that is a precursor of the two isomeric diols. Metabolite C appears to be a conjugate of metabolite A formed by esterification of the 4'-hydroxy group with a hydroxylated aro- matic acid. The lack of a metabolite of pyrethrin II 2646 -347- I. YAMAMOTO, M. ELLIOTT & J. E. CASIDA Structures of pyrethrin 1, pyrethrin 11, allethrin, and their metabolites GENERAL FORMULA R RR'yC H3 CH3CH t~~~~~~~~R" 3 O c 0~~~ 11 0 Substituents Designation R R' R" PYRETH RINS c pyrethrin I CH3 CH3 -CH2-CH=CH-CH=CH2 C pyrethrin 11 CO2CH3 CH3 -CH2-CH=CH-CH=CH2 C pyrethrin metabolite A CO2H CH3 -CH2-CH=CH-CHOH-CH2OH pyrethrin metabolite B C02H CH3 -CH2-CHOH-CH=CH-CH2OH C pyrethrin metabolite C CO2H CH3 -CH2-CH=CH-CH-O-conj. CH20H pyrethrin metabolite D C02H CH3 -CH2-CH=CH-CH=CH2 ALLETH RI N allethrin CH3 CH3 -CH2-CH=CH2 allethrin metabolite A' CO2H CH3 -CH2-CHOH-CH20H allethrin metabolite B' CO2H CH3 -CHOH-CH=CH2 allethrin metabolite C' CO2H CH20H -CH2-CH=CH2 allethrin metabolite D' CO2H CH3 -CH2-CH=CH2 with an intact methoxycarbonyl group is in line with the finding that the radiocarbon in 14CH30- carbonyl-labelled pyrethrin II is expired as "4CO2 in rats. The cyclopropanecarboxylic ester linkage cleaves only to a minor extent, since the same metabolites are detected in the urine by radio- autography of the TLC chromatogram when rats are fed either 3H-alcohol-labelled or 14C-acid-labelled pyrethrin I. The relative abundance of excreted metabolites of pyrethrin I or pyrethrin II from rats, 100 hours after administering the pyrethrin, is as follows: metabolite A, 14-21 %; metabolite B 3-4%; metabolite C, 4-6%; unmetabolized com- pounds, 4-18 %; and unidentified compounds (most- ly polar ones), the remainder. While metabolite D (pyrethrin-wt-oic acid) is formed by microsomal systems prepared from houseflies, it is not detected in the excretions of rats, indicating that it is a transient intermediate in the in vivo metabolism of pyrethrins. The metabolic pathway of allethrin in rats is somewhat similar, but there are important differences. Oxidative attack on the isobutenyl side chain of the acid moiety gives the intermediate mono- allethronyl chrysanthemum dicarboxylate (meta- bolite D'), which, in turn, is metabolized by attack at any one of four positions: hydrolysis to alle- throlone and chrysanthemum dicarboxylic acid to a smaller extent; formation of the 2',3'-diol from the allyl moiety (metabolite A'); hydroxylation at the methylene position of the allyl grouping (metabolite B'); and hydroxylation at one of the gem-dimethyl groups (metabolite C'). All in all, the metabolism of pyrethrins involves (1) some oxidative modification in both the alcohol and the acid moieties, (2) the hydrolysis of the methoxycarbonyl group of pyrethrin II, and, to a smaller extent, (3) the hydrolysis of the ester linkage between the two moieties. These reactions contribute to, or account for, the low toxicity of these compounds for mammals. 348