6 research outputs found
Pulse Packet Stochastic Model for Gastric Emptying in the Fasted State: A Physiological Approach
Fasted-state gastrointestinal (GI)
fluid transit is typically represented
as a first-order, deterministic process (averaged and viewed as a
continuous approximation). It is, however, most likely a discrete
process involving fluid packets interrupted by variable time periods
of little to no fluid emptying. In this report we present a physiologically
based pulsed-packet gastric fluid emptying model and evaluate it with
respect to recent gastrointestinal fluid volume emptying results,
published gastric emptying of various dosage forms, and gastric fluid
emptying as a function of GI motility. We develop the mathematical
model for gastric emptying of discrete volumes emptied during intermittent
pulse times of variable lengths, defined as a function of gastric
motility utilizing a Poisson point process with motility-dependent
intensity. We compare the simulations with observed gastric emptying
results. The discrete pulse packet gastric volumetric emptying model
is a more physiologically realistic mathematical model for gastric
emptying, and it accounts well for the average observed emptying rates
and, importantly, encompasses the variability of of observed volume
and dosage form emptying rates
Utilization of Gastrointestinal Simulator, an in Vivo Predictive Dissolution Methodology, Coupled with Computational Approach To Forecast Oral Absorption of Dipyridamole
Weakly basic drugs exhibit a pH-dependent
dissolution profile in
the gastrointestinal (GI) tract, which makes it difficult to predict
their oral absorption profile. The aim of this study was to investigate
the utility of the gastrointestinal simulator (GIS), a novel in vivo
predictive dissolution (iPD) methodology, in predicting the in vivo
behavior of the weakly basic drug dipyridamole when coupled with in
silico analysis. The GIS is a multicompartmental dissolution apparatus,
which represents physiological gastric emptying in the fasted state.
Kinetic parameters for drug dissolution and precipitation were optimized
by fitting a curve to the dissolved drug amount-time profiles in the
United States Pharmacopeia apparatus II and GIS. Optimized parameters
were incorporated into mathematical equations to describe the mass
transport kinetics of dipyridamole in the GI tract. By using this
in silico model, intraluminal drug concentrationātime profile
was simulated. The predicted profile of dipyridamole in the duodenal
compartment adequately captured observed data. In addition, the plasma
concentrationātime profile was also predicted using pharmacokinetic
parameters following intravenous administration. On the basis of the
comparison with observed data, the in silico approach coupled with
the GIS successfully predicted in vivo pharmacokinetic profiles. Although
further investigations are still required to generalize, these results
indicated that incorporating GIS data into mathematical equations
improves the predictability of in vivo behavior of weakly basic drugs
like dipyridamole
Improved Protease-Targeting and Biopharmaceutical Properties of Novel Prodrugs of Ganciclovir
The
prodrug strategy has been frequently employed as a chemical
approach for overcoming the disadvantages of existing parent drugs.
In this report, we synthesized four monoester prodrugs of ganciclovir,
an anticytomegalovirus drug, and demonstrated their potential advantages
in protease-targeted activation and biopharmaceutical profiles over
the parent compound. We demonstrated that these four prodrugs of ganciclovir,
i.e., <i>N</i>-benzyloxycarbonyl-(L)-alanine-ganciclovir
(CbzAlaGCV), <i>N</i>-benzyloxycarbonyl-(Ī±,l)-aminobutyric acid-ganciclovir (CbzAbuGCV), <i>N</i>-acetyl-(l)-phenylalanine-(l)-alanine-ganciclovir (AcPheAlaGCV),
and <i>N</i>-acetyl-(l)-phenylalanine-(Ī±,l)-aminobutyric acid-ganciclovir (AcPheAbuGCV), are hydrolytically
activated by the protease of human cytomegalovirus (hCMV), a serine
protease that possesses intrinsic esterase activities. CbzAlaGCV and
AcPheAlaGCV were found to be activated at a higher rate by the hCMV
protease than CbzAbuGCV and AcPheAbuGCV. These ganciclovir prodrugs
could potentially be targeted to selective activation by the hCMV
protease which is only present at the viral infection sites, thereby
achieving higher efficacy and lower systemic toxicity. The tissue
stability, cellular uptake, and trans-epithelial transport of these
ganciclovir prodrugs were also characterized. The <i>N</i>-acetylated dipeptide prodrugs of ganciclovir were found to be generally
more stable than Cbz-amino acid prodrugs in various tissue matrices.
Among the four prodrug candidates, AcPheAbuGCV was the most stable
in human cell homogenates, plasma, and pooled liver microsomes. AcPheAbuGCV
also possessed a superior cellular uptake profile and permeability
across epithelial cell monolayers. Since the targeting and selective
activation of a prodrug is determined by not only its rate of hydrolysis
catalyzed by the hCMV protease target but also its biopharmaceutical
properties, i.e., oral absorption and systemic availability, AcPheAbuGCV
is considered the best overall candidate among the four ganciclovir
prodrugs for further research and development for treatment of hCMV
infection
Establishing the Pharmaceutical Quality of Chinese Herbal Medicine: A Provisional BCS Classification
The Biopharmaceutical Classification
System (BCS), which is a scientific
approach to categorize active drug ingredient based on its solubility
and intestinal permeability into one of the four classes, has been
used to set the pharmaceutical quality standards for drug products
in western society. However, it has received little attention in the
area of Chinese herbal medicine (CHM). This is likely, in part, due
to the presence of multiple active components as well as lack of standardization
of CHM. In this report, we apply BCS classification to CHMs provisionally
as a basis for establishing improved <i>in vitro</i> quality
standards. Based on a top-200 drugs selling list in China, a total
of 31 CHM products comprising 50 official active marker compounds
(AMCs) were provisionally classified according to BCS. Information
on AMC content and doses of these CHM products were retrieved from
the Chinese Pharmacopoeia. BCS parameters including solubility and
permeability of the AMCs were predicted <i>in silico</i> (ACD/Laboratories). A BCS classification of CHMs according to biopharmaceutical
properties of their AMCs is demonstrated to be feasible in the current
study and can be used to provide a minimum set of quality standards.
Our provisional results showed that 44% of the included AMCs were
classified as Class III (high solubility, low permeability), followed
by Class II (26%), Class I (18%), and Class IV (12%). A similar trend
was observed when CHMs were classified in accordance with the BCS
class of AMCs. Most (45%) of the included CHMs were classified as
Class III, followed by Class II (16%), Class I (10%), and Class IV
(6%); whereas 23% of the CHMs were of mixed class due to the presence
of multiple individual AMCs with different BCS classifications. Moreover,
about 60% of the AMCs were classified as high-solubility compounds
(Class I and Class III), suggesting an important role for an <i>in vitro</i> dissolution test in setting quality control standards
ensuring consistent biopharmaceutical quality for the commercially
available CHM products. That is, provisionally, more than half of
the AMCs of the top-selling CHMs included in this study would be candidates
for a bioequivalence (BE) biowaiver, based on WHO recommendations
and EMEA guidelines. Thus a dissolution requirement on these AMCs
would represent a significant advance in the pharmaceutical quality
of CHM today
Substrate-Competitive Activity-Based Profiling of Ester Prodrug Activating Enzymes
Understanding
the mechanistic basis of prodrug delivery and activation
is critical for establishing species-specific prodrug sensitivities
necessary for evaluating preclinical animal models and potential drugādrug
interactions. Despite significant adoption of prodrug methodologies
for enhanced pharmacokinetics, functional annotation of prodrug activating
enzymes is laborious and often unaddressed. Activity-based protein
profiling (ABPP) describes an emerging chemoproteomic approach to
assay active site occupancy within a mechanistically similar enzyme
class in native proteomes. The serine hydrolase enzyme family is broadly
reactive with reporter-linked fluorophosphonates, which have shown
to provide a mechanism-based covalent labeling strategy to assay the
activation state and active site occupancy of cellular serine amidases,
esterases, and thioesterases. Here we describe a modified ABPP approach
using direct substrate competition to identify activating enzymes
for an ethyl ester prodrug, the influenza neuraminidase inhibitor
oseltamivir. Substrate-competitive ABPP analysis identified carboxylesterase
1 (CES1) as an oseltamivir-activating enzyme in intestinal cell homogenates.
Saturating concentrations of oseltamivir lead to a four-fold reduction
in the observed rate constant for CES1 inactivation by fluorophosphonates.
WWL50, a reported carbamate inhibitor of mouse CES1, blocked oseltamivir
hydrolysis activity in human cell homogenates, confirming CES1 is
the primary prodrug activating enzyme for oseltamivir in human liver
and intestinal cell lines. The related carbamate inhibitor WWL79 inhibited
mouse but not human CES1, providing a series of probes for analyzing
prodrug activation mechanisms in different preclinical models. Overall,
we present a substrate-competitive activity-based profiling approach
for broadly surveying candidate prodrug hydrolyzing enzymes and outline
the kinetic parameters for activating enzyme discovery, ester prodrug
design, and preclinical development of ester prodrugs
<i>In Vivo</i> Dissolution and Systemic Absorption of Immediate Release Ibuprofen in Human Gastrointestinal Tract under Fed and Fasted Conditions
<i>In vivo</i> drug dissolution
in the gastrointestinal (GI) tract is largely unmeasured. The purpose
of this clinical study was to evaluate the <i>in vivo</i> drug dissolution and systemic absorption of the BCS class IIa drug
ibuprofen under fed and fasted conditions by direct sampling of stomach
and small intestinal luminal content. Expanding current knowledge
of drug dissolution <i>in vivo</i> will help to establish
physiologically relevant <i>in vitro</i> models predictive
of drug dissolution. A multilumen GI catheter was orally inserted
into the GI tract of healthy human subjects. Subjects received a single
oral dose of ibuprofen (800 mg tablet) with 250 mL of water under
fasting and fed conditions. The GI catheter facilitated collection
of GI fluid from the stomach, duodenum, and jejunum. Ibuprofen concentration
in GI fluid supernatant and plasma was determined by LCāMS/MS.
A total of 23 subjects completed the study, with 11 subjects returning
for an additional study visit (a total of 34 completed study visits).
The subjects were primarily white (61%) and male (65%) with an average
age of 30 years. The subjects had a median [min, max] weight of 79
[52, 123] kg and body mass index of 25.7 [19.4, 37.7] kg/m<sup>2</sup>. Ibuprofen plasma levels were higher under fasted conditions and
remained detectable for 28 h under both conditions. The AUC<sub>0ā24</sub> and <i>C</i><sub>max</sub> were lower in fed subjects
vs fasted subjects, and <i>T</i><sub>max</sub> was delayed
in fed subjects vs fasted subjects. Ibuprofen was detected immediately
after ingestion in the stomach under fasting and fed conditions until
7 h after dosing. Higher levels of ibuprofen were detected in the
small intestine soon after dosing in fasted subjects compared to fed.
In contrast to plasma drug concentration, overall gastric concentrations
remained higher under fed conditions due to increased gastric pH vs
fasting condition. The gastric pH increased to near neutrality after
feedingbefore decreasing to acidic levels after 7 h. Induction of the fed state reduced systemic levels but increased gastric levels of ibuprofen, which suggest that slow gastric emptying and transit dominate the effect for plasma drug concentration. The finding of high levels of ibuprofen in stomach and small intestine 7 h post dosing was unexpected. Future work is needed to better understand the role of various GI parameters, such as motility and gastric emptying, on systemic ibuprofen levels in order to improve <i>in vitro</i> predictive models