Chemistry Reference
In-Depth Information
infancy; however, sampling systems are available using a variety of different platforms.
GI
fluids are sampled by means of a double-lumen catheter, positioned either via the
mouth or the nose into the upper GI tract [54]. Intubation with two catheters allows
the simultaneous assessment of drug concentrations at two intraluminal positions: the
stomach and duodenum or duodenum and upper jejunum. Positioning of the catheters is
usually monitored by means of
uoroscopy. GI
fluids are sampled as a function of time,
typically for a period of 2
4 h following formulation administration. To minimize the
effect of sampling drug on the absorption process, aspirated volumes should be kept to a
minimum, especially when multiple GI sites are sampled and/or plasma concentrations
are determined in parallel [54]. At the time of sampling, enzymatic processes should be
inhibited, nondissolved and/or precipitated drug particles should be separated (centrifu-
gation or
-
filtration), and possible further precipitation should be avoided by diluting the
particle-free sample. The observed drug concentrations can be related to characteristics
of the GI
fluids such as pH, osmolality, viscosity, surface tension, buffer capacity and
concentration of bile salts, phospholipids, and dietary (digestion) products. Using these
tools, Psachoulias et al. delivered acidic solutions of two weak bases, ketoconazole and
dipyridamole, to the stomach and then assessed the compounds in aspirated drug
sample [111]. Both the total drug and the soluble fraction of the drug in the aspirates
were assessed. While the concentration of administered drug sampled from the duode-
num was supersaturated, only limited precipitation was observed. Furthermore, the
degree of precipitation observed
in vivo
seemed to have been overpredicted when using a
transfer model. Importantly, these data were used to further optimize the transfer
model [111]. Walravens et al. assessed the behavior of a commercially available
suspension of posaconazole (Noxa
l
) administered as such in the fasted state, with
a cola-carbonated beverage, with a proton pump inhibitor (PPI), or with a cola-
carbonated beverage and a PPI [112]. In this study both blood levels and GI samples
(gastric and duodenal) were taken to assess
in vivo
behavior of the API and formulation.
Blood levels suggested that coadministration of a cola beverage with 400 mg posaco-
nazole signi
cantly increased drug absorption (AUC increased twofold), while coad-
ministration of the drug with a PPI (esomeprazole 40mg) with or without a cola drink
decreased exposure (with a decrease in AUC of 37 and 19%, respectively). Gastric and
intestinal pH were invariant to dosing of the cola beverage, but both increased in
response to treatment with the PPI. Drug concentrations were increased in the stomach
upon dosing with a cola beverage and were lower in the presence of a PPI. Based on the
variability, intestinal concentrations of posaconazole were not signi
cantly higher after
the cola beverage but were lower after treatment with the PPI. These data may suggest
that the cola beverage has a number of effects. One of these may be a delay in gastric
emptying as a function of the caloric content and other components that increase the
extent of solubilization of posaconazole in the stomach [113]. Intestinal concentrations
of the drug were dramatically lower than those measured in the stomach. This may be due
to several factors including precipitation based on the accompanying pH shift or drug
absorption that removed drugs from the intestine as a function of blood
ow and
permeability. The higher blood levels and lower intestinal levels associated with this
treatment cohort may suggest that supersaturated levels of the drug were generated and
that these were rapidly transferred to the systemic circulation by the applied sink. When
