The Effect of Inflammatory Bowel Disease and Irritable Bowel Syndrome on Pravastatin Oral Bioavailability: In vivo and in silico evaluation using bottom-up wbPBPK modeling.

The common disorders irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD) can modify the drugs' pharmacokinetics via their induced pathophysiological changes. This work aimed to investigate the impact of these two diseases on pravastatin oral bioavailability. Rat models for IBS and IBD were used to experimentally test the effects of IBS and IBD on pravastatin pharmacokinetics. Then, the observations made in rats were extrapolated to humans using a mechanistic whole-body physiologically-based pharmacokinetic (wbPBPK) model. The rat in vivo studies done herein showed that IBS and IBD decreased serum albumin (> 11% for both), decreased PRV binding in plasma, and increased pravastatin absolute oral bioavailability (0.17 and 0.53 compared to 0.01) which increased plasma, muscle, and liver exposure. However, the wbPBPK model predicted muscle concentration was much lower than the pravastatin toxicity thresholds for myotoxicity and rhabdomyolysis. Overall, IBS and IBD can significantly increase pravastatin oral bioavailability which can be due to a combination of increased pravastatin intestinal permeability and decreased pravastatin gastric degradation resulting in higher exposure. This is the first study in the literature investigating the effects of IBS and IBD on pravastatin pharmacokinetics. The high interpatient variability in pravastatin concentrations as induced by IBD and IBS can be reduced by oral administration of pravastatin using enteric-coated tablets. Such disease (IBS and IBD)-drug interaction can have more drastic consequences for narrow therapeutic index drugs prone to gastric degradation, especially for drugs with low intestinal permeability.

The In Vitro, In Vivo, and PBPK Evaluation of a Novel Lung-Targeted Cardiac-Safe Hydroxychloroquine Inhalation Aerogel.

Hydroxychloroquine (HCQ) was repurposed for COVID-19 treatment. Subtherapeutic HCQ lung levels and cardiac toxicity of oral HCQ were overcome by intratracheal (IT) administration of lower HCQ doses. The crosslinker-free supercritical fluid technology (SFT) produces aerogels and impregnates them with drugs in their amorphous form with efficient controlled release. Mechanistic physiologically based pharmacokinetic (PBPK) modeling can predict the lung's epithelial lining fluid (ELF) drug levels. This study aimed to develop a novel HCQ SFT formulation for IT administration to achieve maximal ELF levels and minimal cardiac toxicity. HCQ SFT formulation was prepared and evaluated for physicochemical, in vitro release, pharmacokinetics, and cardiac toxicity. Finally, the rat HCQ ELF concentrations were predicted using PBPK modeling. HCQ was amorphous after loading into the chitosan-alginate nanoporous microparticles (22.7±7.6 µm). The formulation showed a zero-order release, with only 40% released over 30 min compared to 94% for raw HCQ. The formulation had a tapped density of 0.28 g/cm3 and a loading efficiency of 35.3±1.3%. The IT administration of SFT HCQ at 1 mg/kg resulted in 23.7-fold higher bioavailability, fourfold longer MRT, and eightfold faster absorption but lower CK-MB and LDH levels than oral raw HCQ at 4 mg/kg. The PBPK model predicted 6 h of therapeutic ELF levels for IT SFT HCQ and a 100-fold higher ELF-to-heart concentration ratio than oral HCQ. Our findings support the feasibility of lung-targeted and more effective SFT HCQ IT administration for COVID-19 compared to oral HCQ with less cardiac toxicity. Graphical abstract.

The Analysis of Pethidine Pharmacokinetics in Newborn Saliva, Plasma, and Brain Extracellular Fluid After Prenatal Intrauterine Exposure from Pregnant Mothers Receiving Intramuscular Dose Using PBPK Modeling.

BACKGROUND AND OBJECTIVE: Pethidine (meperidine) can decrease labor pain-associated mother's hyperventilation and high cortisol-induced newborn complications. However, prenatal transplacentally acquired pethidine can cause side effects in newborns. High pethidine concentrations in the newborn brain extracellular fluid (bECF) can cause a serotonin crisis. Therapeutic drug monitoring (TDM) in newborns' blood distresses them and increases infection incidence, which can be overcome by using salivary TDM. Physiologically based pharmacokinetic (PBPK) modeling can predict drug concentrations in newborn plasma, saliva, and bECF after intrauterine pethidine exposure. METHODS: A healthy adult PBPK model was constructed, verified, and scaled to newborn and pregnant populations after intravenous and intramuscular pethidine administration. The pregnancy PBPK model was used to predict the newborn dose received transplacentally at birth, which was used as input to the newborn PBPK model to predict newborn plasma, saliva, and bECF pethidine concentrations and set correlation equations between them. RESULTS: Pethidine can be classified as a Salivary Excretion Classification System class II drug. The developed PBPK model predicted that, after maternal pethidine intramuscular doses of 100 mg and 150 mg, the newborn plasma and bECF concentrations were below the toxicity thresholds. Moreover, it was estimated that newborn saliva concentrations of 4.7 µM, 11.4 µM, and 57.7 µM can be used as salivary threshold concentrations for pethidine analgesic effects, side effects, and the risk for serotonin crisis, respectively, in newborns. CONCLUSION: It was shown that saliva can be used for pethidine TDM in newborns during the first few days after delivery to mothers receiving pethidine.

Comparison of pharmacokinetics of two tylvalosin oral formulations in broiler chickens.

The objective of the study was to compare the relative bioavailability and pharmacokinetics of two commercially available oral formulations of tylvalosin prepared for use in broiler chickens (ProviLosinR and AviLosinR ). A total of 36 healthy, broiler chickens were administered a single oral dose (25 mg/kg b.w.) of each formulation in a parallel randomized design. The relative bioavailability of ProviLosinR was 108% compared to AviLosinR . There were no significant differences between ProviLosinR and AviLosinR tylvalosin formulations in the average means of the area under the plasma concentration-time curve, maximum plasma concentrations and time to maximum plasma concentrations. In conclusion, tylvalosin was rapidly absorbed and relatively slowly eliminated after oral administration of a single dose for both formulations. ProviLosinR and AviLosinR can be used interchangeably as therapeutic agents in broiler chickens.

Safety, Tolerability, and Pharmacokinetics of Nebulized Hydroxychloroquine: A Pilot Study in Healthy Volunteers.

Background: Early in the coronavirus disease 2019 (COVID-19) pandemic, hydroxychloroquine (HCQ) drew substantial attention as a potential COVID-19 treatment based on its antiviral and immunomodulatory effects in vitro. However, HCQ showed a lack of efficacy in vivo, and different groups of researchers attributed this failure to the insufficient drug concentration in the lung following oral administration (HCQ is only available in the market in the tablet form). Delivering HCQ by inhalation represents a more efficient route of administration to increase HCQ exposure in the lungs while minimizing systemic toxicity. In this pilot study, the safety, tolerability, and pharmacokinetics of HCQ nebulizer solution were evaluated in healthy volunteers. Methods: Twelve healthy participants were included in this study and were administered 2 mL of HCQ01 solution (equivalent to 25 mg of HCQ sulfate) through Aerogen® Solo, a vibrating mesh nebulizer. Local tolerability and systemic safety were assessed by forced expiratory volume in the first and second electrocardiograms, clinical laboratory results (e.g., hematology, biochemistry, and urinalysis), vital signs, and physical examinations. Thirteen blood samples were collected to determine HCQ01 systemic exposure before and until 6 hours after inhalation. Results: The inhalation of HCQ01 was well tolerated in all participants. The mean value of Cmax for the 12 participants was 9.66 ng/mL. Tmax occurred at around 4.8 minutes after inhalation and rapidly decreased thereafter. The reported systemic exposure was very low with a mean value of 5.28 (0.6-15.6) ng·h/mL. Conclusion: The low systemic concentrations of HCQ01 of 9.66 ng/mL reported by our study compared with 1 µg/mL previously predicted after 200 mg BID oral administration, and the safety and tolerability of HCQ01 administered as a single dose through nebulization, support the assessment of its efficacy, safety, and tolerability in further studies for the treatment of COVID-19.

Impact of Sustained Exogenous Irisin Myokine Administration on Muscle and Myocyte Integrity in Sprague Dawley Rats.

Irisin is an exercise-induced myokine implicated as a fundamental mediator of physical activity benefits. The aim of the present study was to investigate the role of the chronic administration model of irisin on the physiological and molecular status of skeletal muscle. A total of 20 female Sprague Dawley rats (250 ± 40 g) were implanted with an irisin-loaded osmotic pump (5 µg/kg/day) for 42 days; in addition, 3 females received a single subcutaneous injection of irisin (5 µg/kg). On a weekly basis for six weeks, animals were weighed and blood samples were collected. After 42 days, hind muscle biopsies were collected for histology and gene analysis. Serum irisin, clinical biochemistry, and histopathology were quantified and evaluated. Genes encoding for different physiological muscle activities, such as oxidative stress, fatty acid metabolism, muscle hypertrophy, mitochondrial fusion, and aging were assayed. The results showed a significant reduction in body weight percentage and creatine kinase level without affecting the morphological characteristics of skeletal muscle. Significant changes were noted in genes involved in muscle physiological activity, growth, and aging, as well as genes encoding for the antioxidant system, fatty acid oxidation processes, and mitochondrial fusion. In conclusion, exogenous irisin can induce the same physiological and molecular mechanisms that might be induced by exercise.

The Role of Interventional Irisin on Heart Molecular Physiology.

Irisin, encoded by the FNDC5 (fibronectin type III domain containing 5) gene, is a novel myokine that has been implicated as an essential mediator of exercise benefits. Effects of irisin on heart physiology is still ambiguous. This study aimed to evaluate the impact of exogenous administration of irisin on heart physiology and the pharmacokinetic profile of pump-administered irisin. To do so, Sprague Dawley rats were implanted with an irisin-loaded osmotic pump (5 µg/kg/day) for 42 days, and other animals were administered with single bolus subcutaneous injections of irisin (5 µg/kg). Body weights and blood samples were collected weekly for 42 days for serum irisin quantification and histopathology. Clinical biochemistry analyses were performed. Heart mRNA expression was assessed in 26 selected genes. Chronic interventional exogenous irisin significantly reduced body weight without affecting the heart myocyte size and significantly reduced creatine kinase enzyme level. Blood CBC, serum biochemistry, and heart morphology were normal. Gene expression of FNCD5, Raf1, CPT1, IGF-1, and CALCIN, encoding for heart physiology, increased while PGC1, Nox4, and Mfn1 significantly decreased. Nevertheless, irisin increased the expression of cardioprotective genes and inhibited some genes that harm heart physiology. Administration of irisin promotes myocardial functions and could be translated into clinical settings after preclinical profiling.

Therapeutic Drug Monitoring of Vancomycin in Jordanian Patients. Development of Physiologically-Based Pharmacokinetic (PBPK) Model and Validation of Class II Drugs of Salivary Excretion Classification System (SECS).

Vancomycin is a commonly used antibiotic for multi-drug resistant gram-positive infections treatment, especially methicillin-resistant Staphylococcus aureus (MRSA). Despite that, it has wide individual pharmacokinetic variability and nephrotoxic effect. Vancomycin trough concentrations for 57 Jordanian patients were measured in plasma and saliva through immunoassay and liquid chromatography-mass spectrometry (LC-MS/MS), respectively. Plasma levels were within accepted normal range, with exception of 6 patients who showed trough levels of more than 20 µg/ml and vancomycin was discontinued. Bayesian dose-optimizing software was used for patient-specific pharmacokinetics prediction and AUC/MIC calculation. Physiological-based pharmacokinetic (PBPK) vancomycin model was built and validated through GastroPlus™ 9.8 using in-house plasma data. A weak correlation coefficient of 0.2478 (P=0.1049) was found between plasma and saliva concentrations. The suggested normal saliva trough range of vancomycin is 0.01906 to 0.028589 (µg/ml). Analysis of variance showed significant statistical effects of creatinine clearance and albumin concentration on dose-normalized Cmin plasma and saliva levels respectively, which is in agreement with PBPKmodeling. It can be concluded that saliva is not a suitable matrix for TDM of vancomycin. Trough levels in plasma matrix should always be monitored for the safety of patients.

The Development of a PBPK Model for Atomoxetine Using Levels in Plasma, Saliva and Brain Extracellular Fluid in Patients with Normal and Deteriorated Kidney Function.

BACKGROUND: Atomoxetine is a treatment for attention-deficit hyperactivity disorder. It inhibits Norepinephrine Transporters (NET) in the brain. Renal impairment can reduce hepatic CYP2D6 activity and atomoxetine elimination which may increase its body exposure. Atomoxetine can be secreted in saliva. OBJECTIVE: The objective of this work was to test the hypothesis that atomoxetine saliva levels (sATX) can be used to predict ATX brain Extracellular Fluid (bECF) levels and their pharmacological effects in healthy subjects and those with End-Stage Renal Disease (ESRD). METHODS: The pharmacokinetics of atomoxetine after intravenous administration to rats with chemically induced acute and chronic renal impairments were investigated. A physiologically-based pharmacokinetic (PBPK) model was built and verified in rats using previously published measured atomoxetine levels in plasma and brain tissue. The rat PBPK model was then scaled to humans and verified using published measured atomoxetine levels in plasma, saliva, and bECF. RESULTS: The rat PBPK model predicted the observed reduced atomoxetine clearance due to renal impairment in rats. The PBPK model predicted atomoxetine exposure in human plasma, sATX and bECF. Additionally, it predicted that ATX bECF levels needed to inhibit NET are achieved at 80 mg dose. In ESRD patients, the developed PBPK model predicted that the previously reported 65% increase in plasma exposure in these patients can be associated with a 63% increase in bECF. The PBPK simulations showed that there is a significant correlation between sATX and bECF in human. CONCLUSION: Saliva levels can be used to predict atomoxetine pharmacological response.

Development of a Physiologically-Based Pharmacokinetic (PBPK) Model of Nebulized Hydroxychloroquine for Pulmonary Delivery to COVID-19 Patients.

Despite inconclusive evidence, chloroquine (CQ) and hydroxychloroquine (HCQ)are commonly used for the treatment of Corona virus Disease 2019(COVID-19) in critically ill patients.It was hypothesized that HCQ as an aerosol application can reach the antiviral concentration of ~1-5 µM in the alveolar cells which has been proven effective in vitro. A physiologically-based pharmacokinetic (PBPK) model of nebulized HCQ for pulmonary delivery to COVID-19 patients using the Nasal-Pulmonary Module in GastroPlus® V9.7 simulator, in order to calculate the necessary inhalation dose regimen of HCQ, was developed. The physiological, drug disposition, and pharmacokinetic parameters were obtained from the literature and used during model building after optimization using Optimization Module, while oral data was used for validation. The 25 mg BID inhalation dosing was predicted to lead to alveolar HCQ levels of 7 µM (above EC50 of ~1-5 µM), and small plasma levels of 0.18 µM (as compared to plasma levels of 3.22 µM after 200 mg BID oral dosing). However, average contact time (>1 µM) is around 0.5 h in lung parts, suggesting indirect exposure response effect of HCQ.The developed PBPK model herein predicted HCQ levels in plasma and different lung parts of adults after multiple inhalation dosing regimens for 5 days. This in-silico work needs to be tested in vivo on healthy subjects and COVID-19 patients using 12.5 mg BID and 25 mg BID inhalation doses.

Pharmacokinetics and bioavailability of tildipirosin following intravenous and subcutaneous administration in sheep.

Tildipirosin is a semi-synthetic macrolide antibiotic commonly used in cattle and swine to treat bacterial pneumonia. The objective of this study was to investigate the pharmacokinetic profile of tildipirosin after a single intravenous (i.v.) and subcutaneous (s.c.) administration in healthy lambs. Eighteen lambs were randomly divided into three groups (n = 6 each). Lambs received a single s.c. dose of tildipirosin at 4 and 6 mg/kg b.w. in group 1 and 2, respectively. Lambs in group 3 received a single i.v. dose of tildipirosin at 4 mg/kg b.w. Blood samples were collected at 0, 0.5, 0.75, 1.5, 2, 3, 4, 6, 8, 10, 24, 36, 48 hr, and every 24 hr to day 21, and thereafter at day 28 posttildipirosin administration. The plasma concentrations of tildipirosin were determined using high-performance liquid chromatography with tandem mass spectrometry detection (LC/MS/MS). All lambs appeared to tolerate both the intravenous and subcutaneous injection of tildipirosin. Following i.v. administration, the elimination half-life (T1/2 ), mean residence time (MRT), volume of distribution (Vd/F), and total body clearance (Cl/F) were 119.6 ± 9.0 hr, 281.9 ± 25.7 hr, 521.1 ± 107.2 L, and 2.9 ± 0.5 L/hr, respectively. No significant differences in Cmax (657.0 ± 142.8 and 754.6 ± 227.1 ng/ml), Tmax (1.21 ± 0.38 and 1.35 ± 0.44 hr), T1/2 (144 ± 17.5, 156.5 ± 33.4 hr), and MRT (262.0 ± 30.2 and 250.6 ± 54.5 hr) were found in tildipirosin after s.c. dosing at 4 and 6 mg/kg b.w., respectively. The absolute bioavailability (F) of tildipirosin was 71.5% and 75.3% after s.c. administration of 4 and 6 mg/kg b.w., respectively. In conclusion, tildipirosin was rapidly absorbed and slowly eliminated after a single s.c. administration in healthy lambs. Tildipirosin could be used for the treatment and prevention of respiratory bacterial infections in sheep. However, further in vitro and in vivo studies to determine the efficacy and safety are warranted. To our knowledge, this is the first study to determine the tildipirosin pharmacokinetic parameters in sheep plasma.

A Novel Eutectic-Based Transdermal Delivery System for Risperidone.

This paper reports for the first time the possible formation of a novel room temperature therapeutic deep eutectic solvent (THEDES) of risperidone (RIS) with some fatty acids, namely capric acid (C10; CA), lauric acid (C12; LA), and myristic acid (C14; MA). All mixtures of RIS and MA yielded a solid or pasty-like solid and were readily discarded. Some of the prepared THEDESs from RIS and CA or LA have spontaneously transformed into a transparent liquid, without any precipitate at room temperature by simple physical mixing of the components. From the DSC thermograms, phase diagrams of the eutectic systems were constructed and the lowest obtained melting point for a RIS:CA mixture was 17°C at 40:60% w/w ratio. While 22°C was recorded as the lowest melting point for RIS:LA at a ratio of 30:70% w/w, solubility improvement of RIS was up to 70,000-fold compared with water. Freeze-drying microscopy provided valuable information regarding the phase change and transitions the drug undergoes as a function of temperature and it clarifies the interpretation of the DSC results and provides valuable evidence of drug crystals co-melting within the fatty acid base. The presence of natural fatty acid as one component of THEDES and the depression in the melting point significantly (P < 0.05) enhanced RIS skin permeation. Rheological studies showed a viscosity temperature dependency of the DES and well fitted to the Arrhenius equation. Application of the obtained THEDES on the shaved skin of rats revealed the absence of any irritation or edema effects.

Saliva versus Plasma Therapeutic Drug Monitoring of Gentamicin in Jordanian Preterm Infants. Development of a Physiologically-Based Pharmacokinetic (PBPK) Model and Validation of Class II Drugs of Salivary Excretion Classification System.

Gentamicin has proven to be a very successful treatment for bacterial infection, but it also can cause adverse effects, especially ototoxicity, which is irreversible. Therapeutic drug monitoring (TDM) in saliva is a more convenient non-invasive alternative compared to plasma. A physiologically-based pharmacokinetic (PBPK) model of gentamicin was built and validated using previously-published plasma and saliva data. The validated model was then used to predict experimentally-observed plasma and saliva gentamicin TDM data in Jordanian pediatric preterm infant patients measured using sensitive LCMS/MS method. A correlation was established between plasma and saliva exposures. The developed PBPK model predicted previously reported gentamicin levels in plasma, saliva and those observed in the current study. A good correlation was found between plasma and saliva exposures. The PBPK model predicted that gentamicin in saliva is 5-7 times that in plasma, which is in agreement with observed results. Saliva can be used as an alternative for TDM of gentamicin in preterm infant patients. Exposure to gentamicin in plasma and saliva can reliably be predicted using the developed PBPK model in patients.

Pharmacokinetics of toltrazuril and its metabolites in pregnant and nonpregnant ewes and determination of their concentrations in milk, allantoic fluid, and newborn plasma.

The objectives of this study were to determine the pharmacokinetics of toltrazuril and its metabolites in pregnant and nonpregnant ewes following a single oral dose and to determine the plasma concentrations of these compounds in milk, allantoic fluid, and newborn plasma. Eighteen healthy ewes were randomly divided into three groups (n = 6 each): pregnant ewes at 12-13 weeks of gestation (group A), nonpregnant ewes (group B), and pregnant ewes at 1-2 weeks before expected lambing date (group C). Ewes in all groups received a single oral dose of toltrazuril at 20 mg/kg body weight. In groups A and B, blood samples were collected at 1, 3, 5, 7, 9, 12, 15, 18 hr, every 6 hr to day 3, every 12 hr to day 7 and thereafter every 24 hr to day 14 post-toltrazuril administration. In group C, parturition was induced 24-36 hr after toltrazuril administration then milk, allantoic fluid, and newborn plasma samples were collected immediately after birth. Drug metabolites were assayed using ultra high-performance liquid chromatography-ultraviolet detection method (UHPLC-UV). The maximum concentration (Cmax ), area under the plasma concentration-time curve (AUC0-t) , AUC to 24 and 48 hr (AUC0-24 ), and (AUC0-48 ) were significantly higher in pregnant ewes. Longer apparent half-life (T1/2 ), significantly higher apparent volume of distribution (Vd/F) and total clearance (Cl/F) were observed in nonpregnant ewes. The time to maximum plasma concentration (Tmax ), mean residence time (MRT) and elimination rate constant (Kel ) were similar in both groups. The AUC0-24 and AUC0-48 were significantly higher in nonpregnant ewes. The AUC0-t was significantly higher in pregnant ones. The ratio of plasma toltrazuril concentrations in ewes and toltrazuril concentrations in newborn lambs' plasma, allantoic fluid, and milk were 68%, 2.3%, and 5.3%, respectively. Results of this study showed that toltrazuril is well absorbed after a single oral dose in ewes with widespread distribution in different body tissues.

The development of a population physiologically based pharmacokinetic model for mycophenolic mofetil and mycophenolic acid in humans using data from plasma, saliva, and kidney tissue.

BACKGROUND: Mycophenolic acid (MPA) is used widely to prevent graft rejection in kidney-transplant patients. Therapeutic drug monitoring (TDM) in plasma requires an invasive procedure that is inconvenient, especially in pediatric patients. TDM in saliva is a more convenient non-invasive alternative compared with plasma. METHODS: A population physiologically based pharmacokinetic (Pop-PBPK) model of mycophenolate mofetil (MMF) and MPA with enterohepatic recycling was built and verified using previously published plasma, saliva, and kidney biopsy data in healthy and kidney-transplant adult patients. The verified model was then used to predict experimentally observed plasma and saliva MMF and MPA TDM data in Jordanian pediatric kidney transplant patients measured using LC-MS/MS. A correlation was established between plasma and saliva exposures in pediatrics. RESULTS: The developed LCMS was sensitive to both MMF and MPA in plasma and saliva. The developed Pop-PBPK model predicted well the previously reported MMF and MPA levels in plasma, saliva, and kidney tissue and those observed in the current study (more than 75% of observed data points were within 90% predictive interval of population simulations). A statistically significant correlation was found between plasma and saliva exposures for both MMF (Pop-PBPK predicted and observed) and MPA (Pop-PBPK predicted). CONCLUSION: Both MPA and MMF can be classified as class III compounds in the Salivary Excretion Classification System. Saliva is an alternative body fluid to plasma that can be used for TDM of MPA and MMF in kidney-transplant patients in pediatrics. Exposure to MPA and MMF in plasma, saliva, and kidney tissue was reliably predicted using the developed Pop-PBPK model.

Critical pharmacokinetic and pharmacodynamic drug-herb interactions in rats between warfarin and pomegranate peel or guava leaves extracts.

BACKGROUND: In-depth information of potential drug-herb interactions between warfarin and herbal compounds with suspected anticoagulant blood thinning effects is needed to raise caution of concomitant administration. The current study aimed to investigate the impact of co-administration of pomegranate peel and guava leaves extracts, including their quality markers namely; ellagic acid and quercetin, respectively, on warfarin's in vivo dynamic activity and pharmacokinetic actions, in addition to potential in vitro cytochrome P450 enzymes (CYP) inhibition. METHODS: Influence of mentioned extracts and their key constituents on warfarin pharmacodynamic and kinetic actions and CYP activity were evaluated. The pharmacodynamic interactions were studied in Sprague Dawley rats through prothrombin time (PT) and International Normalized Ratio (INR) measurements, while pharmacokinetic interactions were detected in vivo using a validated HPLC method. Furthermore, potential involvement in CYP inhibition was also investigated in vitro on isolated primary rat hepatocytes. RESULTS: Preparations of pomegranate peel guava leaf extract, ellagic acid and quercetin in combination with warfarin were found to exert further significant increase on PT and INR values (p < 0.01) than when used alone (p < 0.05). Pomegranate peel extract showed insignificant effects on warfarin pharmacokinetics (p > 0.05), however, its constituent, namely, ellagic acid significantly increased warfarin Cmax (p < 0.05). Guava leaves extract and quercetin resulted in significant increase in warfarin Cmax when compared to control (p < 0.01). Furthermore, guava leaves extract showed a significant effect on changing the AUC, CL and Vz. Significant reduction in CYP2C8, 2C9, and 3A4 was seen upon concomitant use of warfarin with ellagic acid, guava leaves and quercetin, unlike pomegranate that insignificantly affected CYP activities. CONCLUSION: All combinations enhanced the anticoagulant activity of warfarin as the results of in vivo and in vitro studies were consistent. The current investigation confirmed serious drug herb interactions between warfarin and pomegranate peel or guava leaf extracts. Such results might conclude a high risk of bleeding from the co-administration of the investigated herbal drugs with warfarin therapy. In addition, the results raise attention to the blood-thinning effects of pomegranate peel and guava leaves when used alone.

Effect of Flying at High Altitude on Early Exposure of Paracetamol in Humans.

Pharmacokinetics of paracetamol (APAP) was studied on-board during an air flight and compared to those on ground after 500 mg oral dose in 20 healthy human volunteer in parallel design study. Saliva samples were obtained every 15 min up to 2 h after dosing. Pharmacokinetic parameters were calculated by non compartmental analysis and one compartment models using Winnonlin program V5.2. Results have showed that on-board to ground ratios for area under curves AUC0→1, AUC0→2, time to reach maximum saliva concentration Tmax, absorption rate constant Ka and maximum saliva concentration Cmax were 0.62, 0.38, 1.01, 0.81 and 0.79 respectively. Effective membrane permeability coefficients were optimized by Nelder-Mead algorithm using Simcyp program V13. This showed similar rate of absorption and early exposure up to one hour, and lower bioavailability after 1 h on-board. This can be explained by the increased liver blood flow at high altitude that led to increased liver metabolism on-board. However, APAP elimination parameters were not calculated due to short sampling time. This suggests a need for dose adjustment on-board during long air flights, especially for narrow therapeutic index drugs with flow limited metabolism.

Optimization of Drugs Pharmacotherapy During Pregnancy Using Physiologically Based Pharmacokinetic Models - An Update.

BACKGROUND: Clinical studies during pregnancy are rare due to ethical and practical limitations. Giving pregnant females the same dosing regimen used in adult males or nonpregnant females is inappropriate. Pregnancy physiologically-based pharmacokinetic modeling is a powerful tool that can be used to refine pharmacotherapy during pregnancy. OBJECTIVE: This work provides a review of the current status of application of physiologically based pharmacokinetic models in developing dosing regimens in pregnant women. METHODS: A structured search was done on Scholar Google, Science Direct and PubMed. The articles searched were those providing physiological, anatomical and biochemical data needed for pregnancy physiologically-based pharmacokinetic models or utilizing these models to evaluate the effect of pregnancy on drugs pharmacokinetics. Key words used for search include: PBPK and pregnancy, pharmacokinetic during pregnancy, ethics of pregnancy studies. The found articles were evaluated in terms of main pharmacokinetic features of the drug that were affected by pregnancy, the structure of the model, the software platform used and quality of predicted maternal and fetal exposure. RESULTS: Pregnancy physiologically-based pharmacokinetic models can be used to optimize effective and safe dosing regimens needed during pregnancy. Different model structures have been successfully used for this purpose using different modeling software. CONCLUSION: More work is needed to fill the gaps in knowledge needed to more accurately and mechanistically simulate simultaneous exposure of the pregnant mother and her fetus/ embryo to drugs using pregnancy physiologicallybased pharmacokinetic modeling approach.

Saliva versus Plasma Therapeutic Drug Monitoring of Pregabalin in Jordanian Patients.

The objective is using saliva instead of plasma for pregabalin therapeutic drug monitoring (TDM) since saliva reflects the free non-protein bound drug concentration, simple and noninvasive sampling, cheaper and does not require the expertise of drawing blood. Forty four patients participated in this study, two samples of saliva and another two of blood were taken from each patient; first sample of both saliva and blood is the trough sample and was taken just before the first dose of the day and second sample is the peak sample and was taken 1 h after taking the first dose of the day. Descriptive statistics and t-testing after log transformation were done using Excel, p-value=0.05 was adopted for significant difference. Optimized effective intestinal permeability of pregabalin was estimated by PK-Sim program version 7. This study for the first time revealed that pregabalin is excreted in saliva and classified as class 1 based on Salivary Excretion Classification System (SECS). A good correlation of 0.71-0.83 between Cmin and Cmax of plasma and saliva pregabalin was observed respectively which indicate that saliva sampling is a good alternative matrix for pregabalin TDM. C/D-ratios were calculated to demonstrate pharmacokinetic variability of Pregabalin; the results showed that C/D-ratio was higher in women, elderly and in those patients who had Scr.≥0.9 mg/dl. Proposed pregabalin therapeutic ranges are 0.7 to 1.84 µg/ml in plasma and 0.055 to 0.145 µg/ml in saliva, for neuropathic pain, diabetic neuropathy and disc prolapse patients.