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This study was conducted to compare the ability of two potential microdialysis perfusates to enhance the recovery of SB-265123, a lipophilic, highly protein-bound compound, both in vitro and in vivo. Initial in vitro experiments established that the recovery of SB-265123 by microdialysis using normal saline as a perfusate was poor (1.7%). Different concentrations of Intralipid® and Encapsin® also were evaluated in an identical in vitro setting, to determine enhancement of recovery. In vitro recovery was enhanced to approximately 24 and 65% with 5 and 20% Intralipid®, and to approximately 59 and 62% with 5 and 20% Encapsin®, respectively. A rat in vivo study was conducted with 20% Encapsin® to confirm the in vitro observations. In the in vivo study, 75–80% recovery of free SB-265123 was achieved using 20% Encapsin® as a perfusate. The results from this study indicate that for SB-265123, a lipophilic, highly protein-bound molecule, Encapsin® is an efficient recovery enhancer in vitro. The results from this investigation further demonstrate that a recovery enhancer may be useful for in vivo applications, even with a compound that is highly bound to plasma protein. Copyright © 2002 John Wiley & Sons, Ltd.

Eighteen healthy males received a single 300 mg oral dose of eprosartan as the commercial wet granulation formulation under fasting conditions and following a high-fat breakfast and a single 20 mg intravenous (i.v.) dose. The pharmacokinetics of i.v. eprosartan (mean±S.D.) were characterized by a low systemic plasma clearance (131.8±36.2 mL min−1) and a small steady-state volume of distribution (12.6±2.6 L). Oral bioavailability averaged 13.1%, due to incomplete absorption. In vitro dynamic flow cell dissolution data showed that pH-dependent aqueous solubility of eprosartan is one factor which limits absorption. Eprosartan terminal half-life was shorter after i.v. (approximately 2 h) versus oral (approximately 5–7 h) administration, which may be due to detection of an additional elimination phase or absorption rate-limited elimination following oral administration. Oral administration of eprosartan following a high-fat meal compared with fasting conditions resulted in a similar extent of absorption (based on AUC), but a decreased absorption rate. Cmax was approximately 25% lower, and a median delay of 1.25 h in time to Cmax was observed when eprosartan was administered with food. These minor changes in exposure are unlikely to be of clinical consequence; therefore, eprosartan may be administered without regard to meal times. © 1998 John Wiley & Sons, Ltd.

OBJECTIVE: To assess the effect of ranitidine on the pharmacokinetics of eprosartan in healthy male volunteers. DESIGN: Single-center, randomized, open-label, two-period, period-balanced, crossover study. PATIENTS: Seventeen healthy men aged 19 to 43 years. INTERVENTION: In each period (separated by a ≥7 d washout), subjects received a single 400-mg oral dose of eprosartan alone, or a single oral dose of eprosartan 400 mg and ranitidine 150 mg on day 4 after 3 days of ranitidine 150 mg twice daily. Serial pharmacokinetic samples were obtained for up to 24 hours following eprosartan dosing. MAIN OUTCOME MEASURES: Plasma and urine eprosartan concentrations during each treatment session. RESULTS: Eprosartan maximum concentration (Cmax), the AUC from time zero to the last quantifiable concentration (AUC0-t), and renal clearance (Clr) values were approximately 7%, 11%, and 4% lower, respectively, when administered with ranitidine compared with eprosartan alone. The 95% CIs for the ratio of eprosartan plus ranitidine compared with eprosartan alone were 0.81 to 1.07, 0.77 to 1.03, and 0.64 to 1.43, for Cmax, AUC0-t, and Clr, respectively, indicating no statistically significant difference between regimens. CONCLUSIONS: Repeated doses of ranitidine did not have a marked effect on the single-dose pharmacokinetics of eprosartan. OBJETIVO: Evaluar el efecto de ranitidina en la farmacocinética de eprosartan en pacientes voluntarios saludables. DISEÑO: Centro sencillo, estudio randomizado, rotulación abierta, dos períodos, período cruzado balanceado. PACIENTES: Díecisiete hombres saludables entre 19 a 43 años. INTERVENCIÓN: En cada período (separado por 7 d o más sín medicamento), los pacientes recibieron una dosis oral de eprosartan 400 mg solamente, o una dosis oral eprosartan 400 mg y ranitidina 150 mg 2 veces al día. Muestras en serie sobre la farmacocinética fueron obtenidas hasta 24 horas después de la dosis de eprosartan. MEDICIÓN DE RESULTADOS: Concentraciones en plasma y orina de eprosartan durante cada período de tratamiento. RESULTADOS: Los valores promedio de concentración máxima (Cmax), ABC0-t, y depuración renal (Clr) de eprosartan fueron aproximadamente 7%, 11%, y 4% más bajo, respectivamente, comparado con eprosartan sólo. En intervalos de un 95% de confianza, la razón de eprosartan y ranitidina comparado con eprosartan sólo fueron 0.81 a 1.07, 0.77 a 1.03, y 0.64 a 1.43 para Cmax, ABC0-t, y Clr, respectivamente, indicando que no hay diferencia estadística entre ambos régimenes. CONCLUSIONES: Dosis repetidas de ranitidina no producen un efecto marcado en la farmacocinética de eprosartan en dosis sencillas. OBJECTIF: Évaluer l'effet de la ranitidine sur la pharmacocinétique de l'éprosartan chez des volontaires sains. DEVIS EXPÉRIMENTAL: Étude à échantillonagealéatoire, ouverte, en chassécroisé comprenant deux périodes, et réalisée dans un seul établissement. PATIENTS: Dix-sept hommes sains, âgés entre 19 et 43 ans. INTERVENTION: Dans chaque période (séparée par 7 j de sevrage thérapeutique), les volontaires reçurent soit une dose unique de 400 mg d'éprosartan, ou une dose unique de 400 mg d'éprosartan et 150 mg de ranitidine au jour 4, suivant l'administration de 150 mg de ranitidine aux 12 heures les 3 premiers jours. Plusieurs échantillons pharmacocinétiques furent obtenus durant les 24 heures suivant l'administration d'éprosartan. MESURES DE L'ÉFFET: Concentrations urinaires et plasmatiques d'éprosartan durant chacune des deux périodes de traitement. RÉSULTATS: Quand l'éprosartan fut administré avec la ranitidine, la concentration maximale, la surface sous la courbe, et la clairance rénale d'éprosartan étaient en moyenne approximativement 7%, 11%, et 4% inférieures, respectivement, aux valeurs obtenues avec l'éprosartan administré seul. Aucune différence statistiquement significative n'a été observée entre l'éprosartan administré avec la ranitidine et l'éprosartan seul. Les intervalles de confiance à 95% pour les rapports des valeurs entre les deux groupes sont pour la concentration maximale 0.81 à 1.07, la surface sous la courbe 0.77 à 1.03, et la clairance rénale 0.64 à 1.43. CONCLUSIONS: L'administration de doses répétées de ranitidine n'a pas démontré d'effet marqué sur la pharmacocinétique d'une dose unique d'éprosartan.

The endothelins (ET) are among the most potent vasoconstrictors identified to date, and have been implicated in such diseases as renal failure, pulmonary hypertension, atherosclerosis, and congestive heart failure. There is currently interest in developing selective antagonists of the ET-A subtype receptor, and one such antagonist is SB-247083 ((E)-[1-butyl-5-[2-(2-carboxyphenyl) methoxy-4-chlorophenyl]-1H-pyrazole-4-yl]-2-[5-methoxydihydrobenzofuran-6-yl]methyl]-2-propionic acid). This investigation was conducted to evaluate the preclinical pharmacokinetics of SB-247083. Clearance of SB-247083 was low to moderate in the rat and monkey, and high in the dog. Oral bioavailability of SB-247083 administered as a solid formulation of the free acid was 24% in the rat, but low in the dog (4%) and the monkey (2%). An extensive in vitro salt form and formulation screen resulted in the identification of a formulation containing the monoarginyl salt with improved dissolution properties. This formulation provided a 2- to 4-fold increase in oral bioavailability in each of the preclinical species. In the dog, this improvement was reversed by the pre-administration of 0.1 N HCl to normalize the achlorhydric fasting dog stomach. These data show that SB-247083 may have suitable drug properties for progression in development. Copyright © 2002 John Wiley & Sons, Ltd.