DL-Methionine (Met) has been conventionally used in swine diets with assumption of similar bioefficacy with L-Met. However, because L-Met is the form that is utilized by animals for protein synthesis, L-Met could, theoretically, be more available. Four experiments were conducted to evaluate L-Met bioavailability in nursery pigs with 21-day growth trials. A total of 105,105,112 and 84 crossbred pigs were used in Exp. 1, 2, 3 and 4, respectively. Each experiment had a low Met basal diet and 3 levels of the Met sources (DL-Met and L-Met). In addition to the basal diet, supplementation levels were 0.053%, 0.107% and 0.160% in Exp. 1, 0.040%, 0.080% and 0.120% in Exp. 2, 0.033%, 0.067% and 0.100% in Exp.3, 0.040%, 0.080% and 0.120% in Exp. 4. Body weight (BW), average daily gain (ADG), average daily feed intake (ADFI), gain: feed (G:F) were measured and plasma urea nitrogen (PUN) was analyzed in blood samples weekly. In Exp. 3 and 4, preference studies were conducted with the basal diet and the second highest level of each Met source. When additional DL-Met or L-Met were supplemented to the basal diet, BW, ADG, ADFI, and G:F ratio increased (P < 0.05). In the comparison between the DL-Met and L-Met diets in Exp. 1, pigs in the L-Met group had greater ADG and G:F ratios in the d 0-7 (P < 0.05) period than those in the DL-Met group. However, there were no differences for the overall experimental period. In Exp. 2, pigs in the DL-Met group had greater BW (P < 0.05), ADG (P < 0.05) and ADFI (P < 0.05) than those in the L-Met group for the overall period whereas no differences were observed in G:F ratios and PUN concentrations. In Exp. 3 and 4, there were no differences in BW, ADG, ADFI, G:F ratios or PUN concentrations between L-Met and DL-Met groups for the overall period. There was no preference exhibited for either the DL-Met or L-Met diet. In the results of relative bioavailability of L-Met to DL-Met, the values was 111.1% for d 0-14 based on the estimation by ADG in Exp. 1; L-Met bioavailability was lower than DL-Met based on all response measures in Exp. 2. However, in Exp. 3, relative bioavailability of L-Met to DL-Met was 100.4, 147.3, and 104.1% for d 0-14 ADG, G:F ratio and PUN concentrations. In Exp 4, the relative bioavailability of L-Met was 92.9, 139.4 and 70.4% for d 0-14 ADG, G:F ratio and PUN concentrations. In conclusion, using L-Met in the nursery diet demonstrated no consistent beneficial effect on ADG, G:F ratio or relative bioavailability compared to conventional DL-Met.

La gestion des sites et sols pollués repose sur l’évaluation des expositions aux contaminants. Le retour d’expérience montre que les voies d’exposition directe, et notamment l’ingestion de terre pour les enfants, engendrent les niveaux de risque les plus élevés. Actuellement, en se basant sur la concentration totale d’un polluant dans le sol, l’évaluation des risques tend à être surprotectrice dans la mesure où seule une fraction de la substance peut pénétrer à l’intérieur de l’organisme. L’objectif de l’étude est de mettre en évidence que le test in vitro UBM (Unified Barge Method) de bioaccessibilité est pertinent pour estimer la fraction biodisponible des ETM dans les sols. Pour cela, il est nécessaire de démontrer que la solubilisation des contaminants dans le tractus gastro-intestinal est une étape limitante dans le processus de biodisponibilité et d’autre part que les mesures de bioaccessibilité sont corrélées aux mesures de biodisponibilité. Pour 15 sols sélectionnés sur trois sites contaminés différents, l’étude montre que la biodisponibilité est très variable pour le plomb (8% à 82%), le cadmium (12% à 91%) et l’arsenic (3% à 78%). Pour l’antimoine, les valeurs de biodisponibilité relative et de bioaccessibilité sont très faibles indépendamment des caractéristiques contrastées des sols (valeurs < 20%). De ce fait, ces conditions ne permettent pas de valider le test in vitro pour l’antimoine. Les résultats des corrélations, pour les trois autres contaminants, démontrent que la bioaccessibilité est l’étape limitante de la biodisponibilité et que le test UBM est pertinent pour estimer la bioaccessibilité de ces éléments dans les sols. Notre étude met également en évidence l’impact de la matrice sol sur les variations des valeurs de bioaccessibilité. Ainsi, il a été montré que la distribution des contaminants sur les différentes phases porteuses du sol est un paramètre majeur et robuste pour expliquer les variations de la bioaccessibilité pour l’ensemble des sols étudiés. Les résultats de l’étude mettent en lumière que le test in vitro UBM peut fournir une alternative possible aux investigations in vivo afin d’affiner les niveaux d’exposition des ETM suite à l’ingestion de sol / The management of contaminated soil is based on the assessment of exposure of pollutants. The review shows that the direct routes of exposure, including soil ingestion for children, generate the highest risk levels. Currently, based on the total pollutant concentration in soil, risk assessment tends to be overestimate because only a fraction of the substance may penetrate into the body. The aim of the study is to demonstrate that in vitro UBM test (Unified Method Barge) is relevant to estimate the bioavailable fraction of metals in the soil by estimating the bioaccessible fraction. For this, it is necessary to show that the solubilization of contaminants in the gastrointestinal tract is a limiting step in oral bioavailability process and that bioaccessibility is correlated to bioavailability. For 15 soils selected on three different sites, the study shows that bioavailability is highly variable for lead (8% to 82%), cadmium (12% to 91%) and arsenic (3 % to 78%). For antimony, the relative bioavailability and bioaccessibility values are very low independently of the different soil characteristics (values <20%). Thus, these conditions do not allow to validate in vitro test for antimony. The results of correlations, for the three other contaminants, show that bioaccessibility is the limiting step in the bioavailability process and that UBM test is relevant to estimate the bioaccessibility. Our study also highlights the impact of the soil matrix on the variation of bioaccessibility values. Thus, it was shown that the distribution of contaminants in the different bearing phases of soil is a major and robust parameter to explain the variations of bioaccessibility for all soils studied. The results of the study highlight that the in vitro UBM test is a promising alternative to in vivo investigations to measure the exposure levels of metals after soil ingestion

Le chlordécone est un pesticide organochloré, qui a été utilisé dans les Antilles françaises pour lutter contre le charançon du bananier Cosmopolites sordidus. Ce pesticide a été interdit en 1993 en raison de sa toxicité et de sa persistance dans l'environnement. Cependant des études ont montré que la population antillaise continue d'être exposée (lait maternel et sang contaminés, transfert de chlordécone mère-jeune, retard du développement cognitif, risque de cancer de la prostate) en particulier via l'alimentation. Depuis 2008, la réglementation européenne n°396/2005 est appliquée sur le territoire antillais (limite maximale fixée à 10 et 20 µg chlordécone /kg poids frais repsectivement dans le foie et l'oeuf et de 100 µg/kg de matière grasse dans le gras). Il s'avère que la contamination des denrées au chlordécone est due au fait que les sols d'anciennes bananeraies autrefois traités au chlordécone (principalement des andosols, des nitisols et des ferrisols) demeurent contaminés. L'andosol contient de l'argile allophane, structure qui confère une microporosité élevée par l'enchevêtrement de motifs particulaires répétés à plusieurs échelles. Le chlordécone de l'andosol a été potentiellement piégé par ce réseau de micropores et est supposé être fortement retenu. Au contraire, le nitisol contient de l'argile halloysite, dont la structure correspond à une superposition de couches et ménage une faible porosité. Notre hypothèse est que le chlordécone est moins retenu par le nitisol que par l'andosol. Les animaux monogastriques élevés en plein air (porcin, volaille) sont susceptibles d'ingérer du sol de manière involontaire. Chez la poule pondeuse, les niveaux d'ingestion de sol peuvent atteindre 25 % de la ration alimentaire journalière dans le cas d'une réduction du couvert végétal et/ou d'un rationnement alimentaire. L'ingestion de sol pour le porcin a été peu étudiée. Nous avons cherché à déterminer les aptitudes d'un andosol et d'un nitisol à retenir le chlordécone durant le processus digestif. Pour cela nous avons évalué la biodisponibilité relative du chlordécone d'un andosol et d'un nitisol chez l'animal monogastrique. La détermination de la biodisponibilité relative repose sur la comparaison des pentes entre la réponse (concentration de chlordécone dans les matrices animales) obtenue lors des doses croissantes de chlordécone ingérées via la matrice testée (l'andosol ou le nitisol) à la réponse obtenue lors des mêmes doses de chlordécone ingérées via une matrice de référence (huile). Les résultats obtenus chez la poule pondeuse et le porcelet ont indiqué que l'andosol et le nitisol n'affectent pas la biodisponibilité du chlordécone. Ainsi, la biodisponibilité relative du chlordécone des sols étudiés a été identique et considérée égale à 100% aussi bien chez la poule que chez le porcelet. Le chlordécone du sol a donc été extrait durant le processus digestif et absorbé par l'animal monogastrique à l'identique du chlordécone dissous dans de l'huile. Le chlordécone du sol est donc assimilable par l'animal d'élevage. Ainsi, les sols contaminés en chlordécone présentent un réel risque pour la filière animale. Les teneurs en chlordécone des produits (foie, gras, oeuf) ont dépassé les limites maximales acceptables dès lors que les animaux monogastriques ont ingéré 6,8 µg chlordécone /jour/kg de poids vif. Sachant que 10% des sols cultivables contiennent au moins 1 mg chlordécone /kg, dès lors qu'un animal monogastrique (poule pondeuse ou porcelet) ingère 17 % de sol dans sa ration alimentaire quotidienne, les teneurs en chlordécone des produits dépasseront les limites maximales et seront « impropres » à la consommation. Il convient ainsi d'identifier les pratiques d'élevage à risques pour préconiser des mesures limitant la contamination des produits animaux au chlordécone / Chlordecone (CLD) is an organochlorine pesticide used in the French West Indies against black weevil Cosmopolites sordidus. This pesticide was banned in 1993, because of the toxicity and persistence of this compound in the environment. However, several studies indicated that the population is already exposed to chlordecone (contaminated blood and maternal milk, chlordecone transfer to the mother from the child, memory delay in child and risk to the prostate cancer) particularly by food ingestion. Since 2008, European Regulation °396/2005 is applied in French West Indies (maximal limit fixed at 10 and 20 µg chlordecone/kg of fresh weight in liver and egg and at 100 µg chlordecone /kg of fat in fat). Soils of banana crops previously treated by chlordecone (mainly andosols, nitisols, ferrisols) are still contaminated and are the major source of contamination of food products. Andosol contains allophane clay structure which allows a high microporosity with the formation of particle aggregates in a pattern repeated at different scales. chlordecone would be strongly trapped by this micropores structure and supposed to be strongly retained. Nitisol contains halloysite clayed structure composed to the clay layers superposition with a low porosity. Our hypothesis is that chlordécone is less retained by nitisol than by andosol. Monogastric animals reared outside (pig, poultry) may involuntary ingest soil. It has been shown that hen can ingest soil amounts corresponding to 25 % of the daily ration in the case of vegetation reduction and of nutritional imbalance. Soil ingestion by pig was less studied. In the frame of this research work, we determined andosol and nitisol capacities to retain chlordecone during the digestive process. The relative bioavailability of soil-bound chlordecone in monogastric farm animals (laying hen and juvenile swine) was established. The relative bioavailability determination consists to the slope comparison between the response (concentrations of chlordecone in animal matrices) obtained with increasing chlordecone doses via andosol or nitisol and the response obtained with the same chlordecone ingestion doses via a reference matrix (oil). Results showed that andosol and nitisol did not reduce the chlordecone bioavailability. Thus, relative bioavailability of soil-bound chlordecone was considered to be equal to 100% in laying hen and in juvenile swine. chlordecone was extracted during the digestive process and was absorbed by the monogastric animals. Thus, soil-bound chlordecone is directly assimilated by monogastric farm animals. Concentrations of chlordecone in animal products (liver, fat, egg) exceeded maximal limits for a chlordecone ingestion at least equal to 6.8 µg chlordecone/day/kg of body weight. Since 10% of agricultural soils are contaminated with at least 1 mg/kg, the ingestion of 17% of soil in the daily food ration will result in animal products not acceptable for human consumption. Therefore, it is important to characterize the risk livestock farming practices in order to limit the contamination of food products

Les polychlorobiphényles (PCB) et notamment les congénères les plus présents dans les sites et sols pollués, les PCB non dioxin like, constituent un danger sanitaire potentiel. Le risque associé est exacerbé chez le jeune enfant (6 mois à 3 ans) du fait, notamment, de son comportement exploratoire qui, de plus, a lieu durant une période critique de la croissance. L'objectif principal de cette thèse a été de caractériser l'impact des caractéristiques du sol sur la biodisponibilité relative des PCB. Les résultats in vivo ont montré l'impact des caractéristiques de la matière organique des sols sur la biodisponibilité relative des PCB par l'emploi de sols artificiels. Plusieurs matières organiques standardisées ont été testées allant des matières organiques solubles (acides fulviques, acides humiques) à une matière organique à la condensation maximale : le charbon actif. Ces éléments ont permis de montrer de larges variations de biodisponibilité relative allant d'une biodisponibilité relative nulle (charbon actif) à 100% (acide fulvique). Ces données soulignent l'importance de la condensation de la matière organique dans la rétention des PCB durant les processus digestifs. L'impact de caractéristiques (contenu en carbone organique, argile, black carbon, pH, concentrations en PCB) de sols historiquement contaminés sur la biodisponibilité a ensuite été évalué. Le taux de carbone organique et en black carbon sur la rétention des PCB. Toutefois la biodisponibilité relative demeure supérieure à 45% quel que soit le sol étudié. Les PCB sont donc peu retenus par le sol. Ainsi, l'exposition aux PCB via l'ingestion de sol semble proportionnelle à la quantité ingérée / Polychlorobiphenyls (PCBs) and, overall, non-dioxin-like PCBs (NDL-PCBs) the most abundant congeners in contaminated environmental matrices, constitute a potential health hazard. This risk is even more acute for young children (6 month to 3-year-old) because of their mouthing activities and because this exposure occurs during a critical part of their growth. The main objective of this thesis was to characterise the impact of soil's characteristics on the relative bioavailability of PCBs. The impact of the soil organic matter characteristics on the relative bioavailability of PCBs was assessed using artificial soils. Several standardised organic matters were tested ranging from soluble organic matters (fulvic acids, humic acids) to one organic matters highly condensed, activated carbon, a model of black carbon. These elements lead to show important variations in terms of relative bioavailability from 0% (activated carbon) to 100%, maximal relative bioavailability (fulvic acids). These findings highlight the importance of OM condensation in terms of PCB retention during the digestive processes. Then, the Impact of organic carbon, black carbon and clay content, pH, NDL-PCBs concentrations in historically contaminated soils on bioavailability and bioaccessibility was assessed. These approaches tended to show the importance of OC and BC content on retention of PCBs. Relative bioavailability was found to be higher than 45%, whatever the soil. Thus, PCBs retention in contaminated soils appears rather limited. Finally, exposure to PCBs via soil ingestion appears proportional to the quantity ingested

Lamivudina (3TC) e zidovudina (ZDV) são inibidores nucleosídeos da transcriptase reversa utilizados na terapêutica anti-HIV. Para avaliar a equivalência farmacêutica entre um medicamento teste contendo esta associação e o referência, foi desenvolvido um método para determinação cromatográfica simultânea de 3TC e ZDV em comprimidos. O método empregou coluna C8 Shim-pack&#174;(150 x 4,6 mm, 5 &#181;m), pré-coluna C18 Phenomenex&#174; (50x4,6 mm 5um), água e metanol 60:40 (v:v) como fase móvel e detecção a 266nm. Este mostrou-se específico, com linearidade entre 45 a 5000 ng/mL, precisão demonstrada por CV% inferior a 5%, exatidão entre 90,0 e 110,0% com recuperação superior a 90% para ambos os fármacos. Os testes de dissolução apresentaram porcentagem de cedência média superior a 85% em 30 minutos. A biodisponibilidade relativa dos produtos Biovir&#174; (referência) e Lamivudina + Zidovudina 150 + 300 mg (teste), foi avaliada por meio de um estudo quantitativo direto, cruzado e aberto. Para purificação das amostras biológicas contendo 3TC e ZDV foi realizada adição de acetato de amônio e dupla extração com acetato de etila. O método cromatográfico bioanalítico utilizou coluna C8 Shim-pack&#174; (150 x 4,6 mm 5 &#181;m) e pré-coluna C18 Phenomenex&#174; (50 x 4,6 mm; 5 &#181;m). Empregou-se sistema gradiente linear, combinando fase móvel A, tampão fosfato 0,01 M:acetonitrila (97:3 v/v) e fase móvel B, metanol, sob fluxo de 1,0 mL/min e detecção a 270 nm. Utilizou-se como padrão interno solução 10 &#181;g/mL de estavudina. O método mostrou-se linear na faixa de concentração de 80 a 2500 ng/mL para 3TC e 80 a 5000 ng/mL para ZDV, com adequada precisão e exatidão intra-corridas e inter-corridas. As amostras plasmáticas mostraram-se estáveis a pelo menos três ciclos de congelamento e descongelamento e 48 horas à temperatura ambiente, após preparação. Os parâmetros farmacocinéticos calculados para 3TC foram: ASCo-t de 4936,10 ng.h/mL e 4760,07 ng.h/mL, ASCo-&#8734; de 5305,76 ng.h/mL e 5069,16 ng.h/mL; Cmax de 1526,33 ng/mL e 1585,61 ng/mL e tmax 1,04 h e 0,97 h, respectivamente, para os produtos referência e teste. Para ZDV os valores obtidos foram ASCo-t de 2341,32 ng.h/mL e 2538,17 ng.h/mL, ASCo-&#8734; de 2561,68 ng.h/mL e 2770,21 ng.h/mL e Cmax de 2406,56 ng/mL e 2652,80 ng/mL e tmax 0,60 h e 0,55 h, respectivamente, para os produtos referência e teste. Os intervalos de confiança 90% para as relações entre os parâmetros Cmax, ASCo-t e ASCo-&#8734; em escala logarítmica obtidos para ambos os fármacos após administração dos produtos referência e teste a 24 voluntários sadios, estiveram compreendidos entre os limites de 80 a 125% exceto pelo Cmax para ZDV. O coeficiente de variação intra-sujeito de 47% demonstrou a alta variabilidade da ZDV em relação ao Cmax. Estudos de permeabilidade indicaram que a ZDV tem alta permeabilidade e alta solubilidade (Classe I) e a 3TC apresenta moderada permeabilidade e alta solubilidade (Classe III) . A absorção destes não é afetada significativamente pelas glicoproteínas-P, o que não pode explicar a alta variabilidade in vivo da absorção de ZDV. / Lamivudine (3TC) and zidovudine (ZDV) are the nucleoside reverse transcriptase inhibitors, They are used in combinations of antiretroviral therapy. The switchability between one test product and reference could be proved if they are pharmaceutically equivalents and bioequivalents. This research beginning with development and validation of chromatographic method to 3TC and ZDV simultaneous determination in tablet. The HPLC system were used to assay and 266nm wavelength ultraviolet detector. Separation was performed using a C8 column (150 x 4,6 mm, 5 &#181;m) Shim-pack&#174;protected by a C18 column (50 x 4,6 mm, 5 &#181;m) Phenomenex&#174;. The mobile phase is composed of water and methanol 60:40 (v:v). This method was successfully applied to simultaneous determination to 3TC and ZDV without interference. It was validated over the range of 45 a 5000 ng/mL for both drugs with accurate from 90 to 110% and precision with variation lower than 5%. Extraction recoveries of the analytes were higher than 90%. The mean dissolution data about 3TC and ZDV were above than 85% in 30 minutes of dissolution test. The relative bioavailability between Biovir&#174; (brand-name product) and Lamivudina + Zidovudina 150 + 300 mg (test product), was conducted for one direct quantitative, open and crossover study. The serial plasma sample of 3TC and ZDV collected after oral administration of brand-name product and test product, were analyzed using a validated high-performance liquid chromatography assay with UV detection in wavelength of 270 nm. The double liquid-liquid extraction was realized with additions of amonio acetat. A CLC-C8 (M) column (150 x 4,6 mm 5 &#181;m) Shim-pack&#174;and C18 column (50 x 4,6mm 5 &#181;m) Phenomenex&#174;, was eluted with two mobile phase in a linear gradient system at a flow-rate of 1 mL/min. The mobile phase A was composed by 0,01 M phosphate bufer:acetonitrile (97:3 v/v) and mobile phase B composed by methanol. A methanolic solution containing 10 &#181; g/mL of stavudine was used as internai standard. The method was linear over the range of 80 a 2500 ng/mL for 3TC and 80 a 5000 ng/mL for ZDV. It was shown adequate intra-day accuracy; inter-day accuracy and precision. The sample have been stable in three cycle of freezing and thawing and 48 hours in room temperature after thawing, purified and with mobile phase. The pharmacokinetic parameter estimates for 3TC, were: ASCo-t de 4936,10 ng.h/mL e 4760,07 ng.h/mL, ASCo-C/) de 5305,76 ng.h/mL e 5069,16 ng.h/mL; Cmax de 1526,33 ng/mL e 1585,61 ng/mL e tmax 1,04 h e 0,97 h, respectively for brand-name product and test product. The obtained values for ZDV were: ASCo-t de 2341 ,32 ng.h/mL e 2538,17 ng.h/mL, ASCo-if.l de 2561,68 ng.h/mL e 2770,21 ng.h/mL e Cmax de 2406,56 ng/mL e 2652,80 ng/mL e tmax 0,60 h e 0,55 h respectively for for brand-name product and test product. The 90% confidence intervals for Cmax, ASCo-t e ASCo-&#8734; for log¬transformed results for 3TC and ZDV after oral administration of brand-name product and test product to 24 health volunteers was between 80 to 125% except for Cmax of ZDV. The high variability of Cmax this was displayed by intra-individual coefficient of variation of 47%. Permeability results suggest that ZDV has a high permeability and high solubility (Class I) and Lamivudine presents moderate permeability and high solubility. (Class III). These results assume that P-gp do not affect significantly lamivudine and zidovudine absorption and can not explain the high variability of zidovudine absorption.

Lamivudina (3TC) e zidovudina (ZDV) são inibidores nucleosídeos da transcriptase reversa utilizados na terapêutica anti-HIV. Para avaliar a equivalência farmacêutica entre um medicamento teste contendo esta associação e o referência, foi desenvolvido um método para determinação cromatográfica simultânea de 3TC e ZDV em comprimidos. O método empregou coluna C8 Shim-pack&#174;(150 x 4,6 mm, 5 &#181;m), pré-coluna C18 Phenomenex&#174; (50x4,6 mm 5um), água e metanol 60:40 (v:v) como fase móvel e detecção a 266nm. Este mostrou-se específico, com linearidade entre 45 a 5000 ng/mL, precisão demonstrada por CV% inferior a 5%, exatidão entre 90,0 e 110,0% com recuperação superior a 90% para ambos os fármacos. Os testes de dissolução apresentaram porcentagem de cedência média superior a 85% em 30 minutos. A biodisponibilidade relativa dos produtos Biovir&#174; (referência) e Lamivudina + Zidovudina 150 + 300 mg (teste), foi avaliada por meio de um estudo quantitativo direto, cruzado e aberto. Para purificação das amostras biológicas contendo 3TC e ZDV foi realizada adição de acetato de amônio e dupla extração com acetato de etila. O método cromatográfico bioanalítico utilizou coluna C8 Shim-pack&#174; (150 x 4,6 mm 5 &#181;m) e pré-coluna C18 Phenomenex&#174; (50 x 4,6 mm; 5 &#181;m). Empregou-se sistema gradiente linear, combinando fase móvel A, tampão fosfato 0,01 M:acetonitrila (97:3 v/v) e fase móvel B, metanol, sob fluxo de 1,0 mL/min e detecção a 270 nm. Utilizou-se como padrão interno solução 10 &#181;g/mL de estavudina. O método mostrou-se linear na faixa de concentração de 80 a 2500 ng/mL para 3TC e 80 a 5000 ng/mL para ZDV, com adequada precisão e exatidão intra-corridas e inter-corridas. As amostras plasmáticas mostraram-se estáveis a pelo menos três ciclos de congelamento e descongelamento e 48 horas à temperatura ambiente, após preparação. Os parâmetros farmacocinéticos calculados para 3TC foram: ASCo-t de 4936,10 ng.h/mL e 4760,07 ng.h/mL, ASCo-&#8734; de 5305,76 ng.h/mL e 5069,16 ng.h/mL; Cmax de 1526,33 ng/mL e 1585,61 ng/mL e tmax 1,04 h e 0,97 h, respectivamente, para os produtos referência e teste. Para ZDV os valores obtidos foram ASCo-t de 2341,32 ng.h/mL e 2538,17 ng.h/mL, ASCo-&#8734; de 2561,68 ng.h/mL e 2770,21 ng.h/mL e Cmax de 2406,56 ng/mL e 2652,80 ng/mL e tmax 0,60 h e 0,55 h, respectivamente, para os produtos referência e teste. Os intervalos de confiança 90% para as relações entre os parâmetros Cmax, ASCo-t e ASCo-&#8734; em escala logarítmica obtidos para ambos os fármacos após administração dos produtos referência e teste a 24 voluntários sadios, estiveram compreendidos entre os limites de 80 a 125% exceto pelo Cmax para ZDV. O coeficiente de variação intra-sujeito de 47% demonstrou a alta variabilidade da ZDV em relação ao Cmax. Estudos de permeabilidade indicaram que a ZDV tem alta permeabilidade e alta solubilidade (Classe I) e a 3TC apresenta moderada permeabilidade e alta solubilidade (Classe III) . A absorção destes não é afetada significativamente pelas glicoproteínas-P, o que não pode explicar a alta variabilidade in vivo da absorção de ZDV. / Lamivudine (3TC) and zidovudine (ZDV) are the nucleoside reverse transcriptase inhibitors, They are used in combinations of antiretroviral therapy. The switchability between one test product and reference could be proved if they are pharmaceutically equivalents and bioequivalents. This research beginning with development and validation of chromatographic method to 3TC and ZDV simultaneous determination in tablet. The HPLC system were used to assay and 266nm wavelength ultraviolet detector. Separation was performed using a C8 column (150 x 4,6 mm, 5 &#181;m) Shim-pack&#174;protected by a C18 column (50 x 4,6 mm, 5 &#181;m) Phenomenex&#174;. The mobile phase is composed of water and methanol 60:40 (v:v). This method was successfully applied to simultaneous determination to 3TC and ZDV without interference. It was validated over the range of 45 a 5000 ng/mL for both drugs with accurate from 90 to 110% and precision with variation lower than 5%. Extraction recoveries of the analytes were higher than 90%. The mean dissolution data about 3TC and ZDV were above than 85% in 30 minutes of dissolution test. The relative bioavailability between Biovir&#174; (brand-name product) and Lamivudina + Zidovudina 150 + 300 mg (test product), was conducted for one direct quantitative, open and crossover study. The serial plasma sample of 3TC and ZDV collected after oral administration of brand-name product and test product, were analyzed using a validated high-performance liquid chromatography assay with UV detection in wavelength of 270 nm. The double liquid-liquid extraction was realized with additions of amonio acetat. A CLC-C8 (M) column (150 x 4,6 mm 5 &#181;m) Shim-pack&#174;and C18 column (50 x 4,6mm 5 &#181;m) Phenomenex&#174;, was eluted with two mobile phase in a linear gradient system at a flow-rate of 1 mL/min. The mobile phase A was composed by 0,01 M phosphate bufer:acetonitrile (97:3 v/v) and mobile phase B composed by methanol. A methanolic solution containing 10 &#181; g/mL of stavudine was used as internai standard. The method was linear over the range of 80 a 2500 ng/mL for 3TC and 80 a 5000 ng/mL for ZDV. It was shown adequate intra-day accuracy; inter-day accuracy and precision. The sample have been stable in three cycle of freezing and thawing and 48 hours in room temperature after thawing, purified and with mobile phase. The pharmacokinetic parameter estimates for 3TC, were: ASCo-t de 4936,10 ng.h/mL e 4760,07 ng.h/mL, ASCo-C/) de 5305,76 ng.h/mL e 5069,16 ng.h/mL; Cmax de 1526,33 ng/mL e 1585,61 ng/mL e tmax 1,04 h e 0,97 h, respectively for brand-name product and test product. The obtained values for ZDV were: ASCo-t de 2341 ,32 ng.h/mL e 2538,17 ng.h/mL, ASCo-if.l de 2561,68 ng.h/mL e 2770,21 ng.h/mL e Cmax de 2406,56 ng/mL e 2652,80 ng/mL e tmax 0,60 h e 0,55 h respectively for for brand-name product and test product. The 90% confidence intervals for Cmax, ASCo-t e ASCo-&#8734; for log¬transformed results for 3TC and ZDV after oral administration of brand-name product and test product to 24 health volunteers was between 80 to 125% except for Cmax of ZDV. The high variability of Cmax this was displayed by intra-individual coefficient of variation of 47%. Permeability results suggest that ZDV has a high permeability and high solubility (Class I) and Lamivudine presents moderate permeability and high solubility. (Class III). These results assume that P-gp do not affect significantly lamivudine and zidovudine absorption and can not explain the high variability of zidovudine absorption.