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Genetic effects of phenoxyacid herbicides and clofibrate in mammalian cells in vivo and in vitro
TRE EETECT OF CAPSULE AGE AND SIZE ON TRB BIOAVAILABILITY OF SALICYLIC ACM IN BEAGLE DDGS
CHERRY, I.D. AND VAN LIER, R.B.L., GReENFIELD, IN 46140
TOXICOLOGYDIVISION, LILLY RESEARCHLABORATORIES,
The toxicology of msny pharmsceuticals and pesticide products has been1 studied by oral Oral administration to dogs in tbir laboratory is administration to bcalle dogs. often lccompliahcd by using relatively larsc number 12 veterinary gelaitin capsules which The purpose of the present are approximately I# inch in lengthand + inch in diameter. acid ia besale dogs when given study was to compare the bioaveilability of 14C-salicylic in either a fresh (less than one month old), or aged (two years) number 12 capsule, or in Salicylic acid was choaen since itr rapid pastric absorption would a number 00 caprule. be more IreaLly affected by slow dissolution of the capsule than a neutral or basic Three groups of two dogs each were given 10 me/kg (0.1106 flCi/mp) ‘*II-salicylic compound. acid in a three-way cross-over study so that each group received a different capsule type A three-day recovery period was allowed between each phase of the on a riven day. ilasu samples~were obtained from each dog at 0, 10, 20, and 40 minutes and xperiwnt. 1. 18. 2. 2#. 3, 5. 7. 12. and 24 hours after each dose. The radiocarbon content of each The following &pie was detcrmined~and the microgram equivslents per ml calculated. peak plasma level, time to peak parsmeterr were evaluated for each dog after esch dose: plssms level, teninal half-life, ares under the plssms level-time curve (AUC), plasma No statistically significant differences clesrance, and spparent voluw of distribution. occurred for my of the psrameters calculated or for mean plssms levels at each of the Average peak plasna levels of 44 &ml were time points for any of the cspsule types. The mean terminal half-life was 2.7 reached at approximately 1.7 hours after dosing. hours, the mesn AUC vas 323 pg-hr/ul, mesa plasms clearsace was 32 ml/hr, and the mean The data suggest that fresh or aged number 12 volums of distribution was 121 ml/kg. veterinary capsules when sdministered to beagle dogs do not impede the absorption of a drug such as sslicylic acid.
l
LIMMMWi, = sPresmt
K.,
AH) VAINIO, II.*
CF mATI_ HWLZH, m address: International +ncy
for
1, SF-00290 Ii&SINK1 29, FDITAND Rexear& on Cancer, Lyon, France
B rink of moft-tinsue sanxlnasa?ldlmliqnnntlyrrphcnFlshssbeenreportedarKsl9 WXkeru occupationnl1y expomud to plenwyacetlc acid herbicides 2,4-D and KPA (1). FMsXyacid herbicides arm not, m, xutagenlc in a variety of bscterial xutsqeuicity assays (2).Fhemxplceticacidsam strmtwal analoquesof a hypolipidendc drug
cloflbmte,lklttMalsohasshClwntopossesscarcinogenic prcpmdswithoutbeinglultagenic in bacterial assays(3). Dscently, 2,4-D and K!PA have teen found to havm hypolipidssnic eff_aswsll pe&cx_~
(41, and m, sixlllarly to clofibrate, 1_ indhlce proliferation of in liver cells of m (4,s). m further clarify the possible genataxic cam@rcialp1xa%&sof2,4-DandMcpA,andtoaoparr?tiss1tothose0f Clofibta~, rse have etuaied ttI!u In&cUon of sister Mtid exchanqex WE) in peri&eral culftpes of Bqpaed rats (100 @kg for 2,4-D and KPA, 200 ng/lcg for clofibrate z?zzE&soxe h-s Blcal dome/disy~, in bone msrra# cells of olinese (treatnents & atria), an5 in CHCIQlls in vitro (10-5, 10-4, and 10-3 M for 1 h). _observed eifther ti bled lyn&xyks Non%nificarItinueaHFsinsCEfn?qnsmc~e~ oftheexpXsedrats,ori.nkaxsmxn-ow dlsofthe~sehamters. Asliqht&~~~xs i!lsfEf raxlencieslE& 7xXezWr. ~isticlnallthetrented(wocellcultllmss~ti
the~andinthe~-ofs9mix).~~~data~rtherindicatesthat
~id~~ides2,4-Dand~,as~asc~~~,donotact~~~darmgingagents.~,the~~gi~~tothesllggest~thatthe~ for trmrrfnitintlcmbytheseagentsimin▭e.g.viaWzeaseBpr&uMcm ofH2D2nna c#ygen radicals (3,s). Wfm: 1) Rikssan M. et al. Dr. J. Induet. wed. 38:27(198111, 2) Seller J. Elutat. Res. 55:197(1978), 3) Redety J.K. et al. m 283:39711980), 4) Vainio H. et al. 6uxxrbl.), 51 Vain&l 8. et al. J. RXk BWlron. Health 8:7OI1982).
CHERRY, I.D. AND VAN LIER, R.B.L., GReENFIELD, IN 46140
TOXICOLOGYDIVISION, LILLY RESEARCHLABORATORIES,
The toxicology of msny pharmsceuticals and pesticide products has been1 studied by oral Oral administration to dogs in tbir laboratory is administration to bcalle dogs. often lccompliahcd by using relatively larsc number 12 veterinary gelaitin capsules which The purpose of the present are approximately I# inch in lengthand + inch in diameter. acid ia besale dogs when given study was to compare the bioaveilability of 14C-salicylic in either a fresh (less than one month old), or aged (two years) number 12 capsule, or in Salicylic acid was choaen since itr rapid pastric absorption would a number 00 caprule. be more IreaLly affected by slow dissolution of the capsule than a neutral or basic Three groups of two dogs each were given 10 me/kg (0.1106 flCi/mp) ‘*II-salicylic compound. acid in a three-way cross-over study so that each group received a different capsule type A three-day recovery period was allowed between each phase of the on a riven day. ilasu samples~were obtained from each dog at 0, 10, 20, and 40 minutes and xperiwnt. 1. 18. 2. 2#. 3, 5. 7. 12. and 24 hours after each dose. The radiocarbon content of each The following &pie was detcrmined~and the microgram equivslents per ml calculated. peak plasma level, time to peak parsmeterr were evaluated for each dog after esch dose: plssms level, teninal half-life, ares under the plssms level-time curve (AUC), plasma No statistically significant differences clesrance, and spparent voluw of distribution. occurred for my of the psrameters calculated or for mean plssms levels at each of the Average peak plasna levels of 44 &ml were time points for any of the cspsule types. The mean terminal half-life was 2.7 reached at approximately 1.7 hours after dosing. hours, the mesn AUC vas 323 pg-hr/ul, mesa plasms clearsace was 32 ml/hr, and the mean The data suggest that fresh or aged number 12 volums of distribution was 121 ml/kg. veterinary capsules when sdministered to beagle dogs do not impede the absorption of a drug such as sslicylic acid.
l
LIMMMWi, = sPresmt
K.,
AH) VAINIO, II.*
CF mATI_ HWLZH, m address: International +ncy
for
1, SF-00290 Ii&SINK1 29, FDITAND Rexear& on Cancer, Lyon, France
B rink of moft-tinsue sanxlnasa?ldlmliqnnntlyrrphcnFlshssbeenreportedarKsl9 WXkeru occupationnl1y expomud to plenwyacetlc acid herbicides 2,4-D and KPA (1). FMsXyacid herbicides arm not, m, xutagenlc in a variety of bscterial xutsqeuicity assays (2).Fhemxplceticacidsam strmtwal analoquesof a hypolipidendc drug
cloflbmte,lklttMalsohasshClwntopossesscarcinogenic prcpmdswithoutbeinglultagenic in bacterial assays(3). Dscently, 2,4-D and K!PA have teen found to havm hypolipidssnic eff_aswsll pe&cx_~
(41, and m, sixlllarly to clofibrate, 1_ indhlce proliferation of in liver cells of m (4,s). m further clarify the possible genataxic cam@rcialp1xa%&sof2,4-DandMcpA,andtoaoparr?tiss1tothose0f Clofibta~, rse have etuaied ttI!u In&cUon of sister Mtid exchanqex WE) in peri&eral culftpes of Bqpaed rats (100 @kg for 2,4-D and KPA, 200 ng/lcg for clofibrate z?zzE&soxe h-s Blcal dome/disy~, in bone msrra# cells of olinese (treatnents & atria), an5 in CHCIQlls in vitro (10-5, 10-4, and 10-3 M for 1 h). _observed eifther ti bled lyn&xyks Non%nificarItinueaHFsinsCEfn?qnsmc~e~ oftheexpXsedrats,ori.nkaxsmxn-ow dlsofthe~sehamters. Asliqht&~~~xs i!lsfEf raxlencieslE& 7xXezWr. ~isticlnallthetrented(wocellcultllmss~ti
the~andinthe~-ofs9mix).~~~data~rtherindicatesthat
~id~~ides2,4-Dand~,as~asc~~~,donotact~~~darmgingagents.~,the~~gi~~tothesllggest~thatthe~ for trmrrfnitintlcmbytheseagentsimin▭e.g.viaWzeaseBpr&uMcm ofH2D2nna c#ygen radicals (3,s). Wfm: 1) Rikssan M. et al. Dr. J. Induet. wed. 38:27(198111, 2) Seller J. Elutat. Res. 55:197(1978), 3) Redety J.K. et al. m 283:39711980), 4) Vainio H. et al. 6uxxrbl.), 51 Vain&l 8. et al. J. RXk BWlron. Health 8:7OI1982).