الفهرس 
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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.