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Abstract Valsartan is an antihypertensive drug which appears as a white or almost white hygroscopic powder. It is a potent, orally active non-peptide tetrazole derivative and acts selectively on AT1, the receptor subtype that mediates the known cardiovascular (CV) actions of angiotensin II, the primary vaso-active hormone of the renin-angiotensin-system which causes reduction in blood pressure. After oral administration of valsartan, maximum concentrations of valsartan in plasma are obtained in 2-4 hours. Its pharmacokinetics is linear in the dose range of 80 to 320 mg so it does not accumulate noticeably in plasma after continuous administration. The mean absolute bioavailability of valsartan is almost 23%, but with great variability. This research was undertaken aiming to characterize membrane transport parameters of valsartan from rabbit intestine adopting single pass perfusion technique in situ, study the anatomical factors which affect the overall absorptive clearance of this compound from different regions of rabbit intestine, examine the potential saturation of transport system on absorptive clearance of this compound from rabbit intestine, as well as the effect of certain absorption enhancers like bile salts and propylene glycol (PG) on the intestinal absorption of this compound. Also, the effect of amlodipine as combination therapy on membrane transport parameters of valsartan from rabbit intestine. Abstract 4 Pharmaceutical Technology department, College of Pharmacy, University of Tanta, Tanta, Egypt. Thus, the work in this thesis comprises the following: 1. Development of a suitable method for analysis of the drugs A sensitive HPLC method was developed for analysis of valsartan. The method was validated for the specificity, linearity, precision, accuracy, limit of detection and limit of quantitation. The chromatographic method was able to quantify valsartan without interference. Valsartan was eluted last at a retention time of 3.13 + 0.02 minutes with losartan as internal standard. These values indicated the absence of any interference. The method was linear in the range of 5 – 40 g/ml for the drugs. The validation results indicated both intraday and interday precision and accuracy. Valsartan was eluted first at a retention time of 4.37 + 0.03 minutes with butyl paraben as internal standard. These values indicated the absence of any interference. 2. Investigation of the regional absorption and existence of saturable transport mechanism of valsartan in rabbit intestine 2.1 Investigation of the regional differences in the absorption of valsartan from rabbit intestine The transport of valsartan was studied at four anatomical region of rabbit intestine namely; duodenum, jejunum, ileum and ascending colon and the results obtained were as follows: The absorptive clearance regularized for the intestinal length in each segment (PeA/L) showed that the absorption of this compound was in the order: ascending colon > duodenum > jejunum > ileum. Abstract 5 Pharmaceutical Technology department, College of Pharmacy, University of Tanta, Tanta, Egypt. where the PeA/L values was (0.0026±0.0002 ml/min.cm) in the duodenum, (0.0022±0.0003 ml/min.cm) in the jejunum, (0.0018±0.0002 ml/min.cm) in the ileum and (0.0095±0.0011 ml/min.cm) in the ascending colon. The fraction absorbed per cm (%Fa/cm) was (0.9203±0.0524) in the duodenum, (0.7866±0.0855) in the jejunum, (0.6473±0.0667) in the ileum and (3.182±0.3146) in the ascending colon. The length required for complete absorption of valsartan (L95%) reached (303.3±20.54cm) in the duodenum, (344.5±38.14cm) in the jejunum, (438.8±59.97cm) in the ileum and (80.84±10.05 cm) in the ascending colon. The transport of valsartan through the transcellular diffusive pathway represented (80.7%, ” " ~ " ”100%, 86.4% and ” " ~ " ”100%) in the duodenum, jejunum, ascending colon and ileum respectively. The transcellular diffusive pathway contributes to the overall absorptive clearance of valsartan from rabbit intestine. This is accredited to the lipophilic nature of valsartan. where the partition coefficient is 1.499, this lipophlicity facilitate the partitioning of valsartan in the phospholipids structure of the cytoplasmic membrane which represent the transcellular diffusive pathway 2.2 Influence of concentration on the absorptive clearance of valsartan from rabbit intestine 2.2.1 At concentration 90μg/ml (0.0207 mM): The PeA/L values for valsartan (0.0207mM) were (0.0027± 0.0001 ml/min.cm) in the duodenum and (0.0023± 0.0003 ml/min.cm) in the Abstract 6 Pharmaceutical Technology department, College of Pharmacy, University of Tanta, Tanta, Egypt. jejunum, while for the control it was (0.0026±0.0002ml/min.cm), (0.0022±0.0003ml/min.cm) in the duodenum and jejunum respectively. 2.2.2 At concentration 160μg/ml (0.37 mM): The PeA/L values for valsartan (0.37mM) were (0.0027± 0.0001 ml/min.cm) in the duodenum and (0.0024± 0.0001 ml/min.cm) in the jejunum, while for the control it was (0.0026±0.0002ml/min.cm), (0.0022±0.0003ml/min.cm) in the duodenum and jejunum respectively The statistical analysis of these results showed non-significant change in the absorptive clearance PeA/L (p-value > 0.05) when concentration increased from 20μg/ml to 90,160μg/ml, which suggest the absence of a saturable carrier transport system for this compound in the anatomical sites studied. Valsartan was reported to have carrier mediated, solute carrier organic anion transporter family member 1B1 and 1B3, which present in the intestine as reported. However, comparing animals and humans, not all membrane transporters are orthologous, meaning that amino acid sequences of transport proteins are among species. Transporters such as OATPs show significant differences between species. 3. Influence of selected absorption enhancers on the absorptive clearance of valsartan in rabbit intestine 3.1 The effect of bile salts Bile salts had significantly promoted the absorptive clearance per unit length (PeA/L) (p-value <0.05) and the percent fraction absorbed per cm (%Fa/cm) of valsartan. |