A PBPK model for chlorecone following dermal application

Podium Presentations-Pharmacokinetics

& Metabolism

The yeast, Succbammycesbotii

(Sb) is used for the treatment of p”domcmbranous colitis. antibiotic-associated dkrhca and Pharmx&netic studies in human volunteers have indkakd high s&y state (SS) fecal levels of Sb are associated with high daily stool output. ‘Ihishassinaban~inratstudieswhertin~tibcrincreases fecal SS Sb kvcb 2-5 fold compared to rats fed fiber&e diets. Hence, we have conducted a number of gastrointesdnal transit studies to investigate theeffe*ofdiduyconditionsonSbIrinctics.Rntsmregivcnafi~r-frce dia or a diet end&cd wftb fihcr-(psytium hydmcolloid) for 8 days. On day 8, snfmak wue dosed orally with Sb (3x10’ CFU) miaed with “Cr-

microspheres (15ptn diam) and killed at predetermined times during the following 48 hr. ‘l%estomach. smaIl intestine, cecum and colon were removed and gut luminal contents weighed, live Sb and “Cr levels were determined in crh of these and feces. Recovery of micnxpbems was generally over !W% and followed the pattern of viable Sb through the intcstks Dktsry fiba appears to incrrclsc the transit of mictosphercs and incressc the Iuminsl content vohune: this e&t incmasal distally along the gut. These data were modeled by compsHmcatsl aoalysis using SAAM II,

wherein the rate of gastrointestinal transit was detemuned by compartmental volume (measumd eaperinmmtally) and the flow rate (defuud by “Cr-nko@aed). ‘Iltc poximrl to distal dispxsion pmdicted by the model was ca~trolled by the number of compartmentsinto which the lumen was dividal. The degree of dis~ion was greatest in the cecum. stomach and duodenumand was less in the lower small intestine and colon.

I Eur. J. Pharm.

Sci. 4 Suppl. (1996) S59-Shl

s59

Upon expossm to chlordeco~~ (CD), workers in pesticide factories have shown overt signs of toxicity afthiT@ the mvous sySU% liver and testes’.

Ithasb&nsllgBcncdthatjuMlilcsanmoreat~thanadults.hence,a whole body distributionstudy was u&r&XlinyoungandadllltF344rsts to determir~ the relative dermal absorption pm&a atxl subsequent pharmacokiaxks of CD. In each group of fern& rats (32 and 82 days). 2.86 pmol cm-’ “C-CD

was pp~fied to clipped skin (2.3% BSA), the area

covmdludtbesnimalsserianyssnifiadwithcolleaionofblooQfeccs, wine and major organs up to 120 hr. By 120 hr. 14.4% and 14.2% applkd CD hsd b&n absorbed in young and aduh tats. nzspuZ+ly. A biophyskslly based percuta~~~~~ model. based on Ihat of Guy et of (1982)b. wss fitted to both sets of data. This model consists of five tirst order rate constants which allow for diffu.kn through the stratumcorneum

and pardtionimgwith the viabk epidermis. Using this model we estimated the nran atmxption time in young and tiult rats as 541.0 and 621.2 hr. respectively. The absorption model was tkn embedded in a whok. body physioloL+al based pharmacokinetk (PBPK) model which summakes the idcmif& tk non-linear datafromthxtcmporallinitedoseexpak#s. components of the system, acts as a predktor for future experiments and qua&% thedlffaencc-s between young a& < in regard to disposition of chlordecone. Upon optimkadon using SAAM II, estimate? were obtained for blood tissue:partitionccef&kns, fecal and urinary eacretion rates and the teamsgoverning uptake of bound chlordcconc by the liver. Of the seven paramztersestimated five wem similarfor young and adults. The PBPK model was verifii at differentdosing levels.

Toximl.22~89-113. ‘P.S. Gumlim(l!X2).A~~Rev.PharmamL ‘Guy.RH.. H&Q,%1. and MaihCk &I. (1982). IWJ. PhannonWics11:119-129.

Agonists with reduced intrinsic activity may be therapeutically useful, since these compounds may have less side effects and increased selectivity of action. In this study tissue-selectivity of CB-alkylamino substituted CPA analogues was investigated by quantification of their hemodynamic and anti-lipolyticeffects on the basis of an integrated pharmacokfnetic-pharmacodynamic (PKIPD) model. Male Wistar rats received intravenous infusions of 1 .O rnmg EmethylaminoCPA (BMCPA), 3.0 mg/kg 8-ethyl-aminoCPA (BECPA), 5.0 m&g EbutylaminoCPA (BBCPA) or vehicle during 15 min. Serial arterial blood samples were drawn for the determination of agonist concentrations and plasma nonestetified fatty acid (NEFA) levels. Blood pressure and heart rate were monitored continuously. Concentration-time profiles of each compound could be described by a bi-expanentfal function. Values for clearance, volume of distribution at steady state and elimination half-fife were 49 i 5,41~4and40f1ml/min!kg,1033f113,705f81and1114f57 ml/kg and 25 f 2, 26 f 2 and 40 f 2 min for BMCPA, 8ECPA and BBCPA, respectively (mean f SEM). Dfferent approaches were used to describe the concentration-effect relationships for heart rate and NEFA. However, both approaches resulted in estimates for potency (EC,) and intrinsic activity (E,) for the compounds in viva. On heart rate the compounds acted as partial agonists, with E, values of -139 f 10, -98 f 18 and -71 f 6 bpm for 8MCPA. BECPA and BBCPA, respectively. On the anti-lipolytic system all three compounds were full agonists and lowered NEFA levels by 74 f 9, 76 f 3 and 77 f 5%, respectively. Furthermore the compounds were more potent on the anti-lipolytic system than on the cardfwascular system. The EC, values for NEFA and heart rate were 57 f 27.78 f 28 and 752 f 131 @ml and 240 f 67,495 f 101 and 916 f 196 nglml for BMCPA, EECPA and 8BCPA, respectively (mean f SEM). This study demonstrates that partial agonists for the adenosine A, receptor may have increased selectfvfty of action in viva.

Pharmacokinetlc/pharmacodynamlc evaluation of anti-lnfectlve agents today is frequently limited to a simple comparison of the in v&o mimmum inhibitory concentration (MIC) with the respective serum concentration of the anti-infective agent. This approach has several major shortfalls. On the pharmacokinetic side. it is necessary to include protein binding in these comparisons since only the free fraction of the drug is pharmacologically active. Furthermore, most infections occur in the extravascular space hence tissue distribution needs to be considered. Experimentally determined ‘total tissue concentrations’ are not good indlcetors of activity since they represent average values including unspecifically bound drug and not the actually present concentrations at the site of action. For the same reason the concept of ‘tissue partition coefficients’ is inadequate since it implies homogenous tissue concentrations. It is the aqueous unbound concentration at the site of infection in the tissue that is most relevant for the magnitude of antibiosis. We determined unbound muscle concentrations experimentally by microdialysis for two model compounds (piperacillin and ceftriaxone) in rats. On the pharmacodynamic side. several approaches to combine MIC with pharmacokinetlc parameters, e.g. time above MIC. C,,,/MIC or AUClMlC have been proposed. However, these are all limited by the fact that MIC IS a unidimensional threshold parameter. We applied an indirect pharmacodynamic E,,-model to quantitate effect-time relatidnships which were experimentally measured by simulation of the previously measured unbound tissue concentrations in vitro and incubation of E. coli. This set-up allowed comparison of the antl-infective potencies of various dosing regimens. It could be shown that for p-lactam antibiotics maximum effects are achieved when the drug is dosed very frequently or after continuous infusion. The pharmacodynamic E,,, model in conjunction with unbound tissue concentrations seems to be a well suited model for the evaluation of anti-infective activity