Modelling the Double Peak Phenomenon in pharmacokinetics

Godfrey, K.R.; Arundel, Philip A.; Dong, Zimeng; Bryant, Robert A.

doi:10.1016/j.cmpb.2010.03.007

Cited by 66 publications

(43 citation statements)

References 21 publications

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“…Amitriptyline pharmacokinetics follows enterohepatic recirculation . In the current study, multiple irregular peaks were observed in the plasma concentration‐time profiles during the absorption phase.…”

Section: Discussionmentioning

confidence: 47%

Quantitative Modeling Analysis Demonstrates the Impact of CYP2C19 and CYP2D6 Genetic Polymorphisms on the Pharmacokinetics of Amitriptyline and Its Metabolite, Nortriptyline

Koh

Pak

Choi

et al. 2018

The Journal of Clinical Pharma

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Amitriptyline is a tricyclic antidepressant that is metabolized mainly by CYP2C19 and CYP2D6 enzymes. Higher plasma levels of amitriptyline and its active metabolite, nortriptyline, are associated with an increased risk of adverse events including anticholinergic effects. The aim of this study was to evaluate the effects of CYP2C19 and CYP2D6 genetic polymorphisms on amitriptyline and nortriptyline pharmacokinetics. Twenty‐four Korean healthy adult male volunteers were enrolled in the study after stratification by their CYP2C19 and CYP2D6 genotypes. Serial blood draws for pharmacokinetic analysis were made after a single oral 25‐mg dose of amitriptyline was administered. Plasma amitriptyline and nortriptyline concentrations were measured by a validated liquid chromatography with tandem mass spectrometry. Population pharmacokinetic modeling analysis was conducted using NONMEM, which evaluated the effects of CYP2C19 and CYP2D6 genotypes on amitriptyline and nortriptyline pharmacokinetics. The biotransformation of amitriptyline into nortriptyline was significantly different between subjects with the CYP2C19*2/*2, *2/*3, and *3/*3 genotypes and those with the other genotypes, with an estimated metabolic clearance of 17 and 61.5 L/h, respectively. Clearance of amitriptyline through pathways other than biotransformation into nortriptyline was estimated as 18.8 and 30.6 L/h for subjects with the CYP2D6*10/*10 and *10/*5 genotypes and those with the other genotypes, respectively. This study demonstrated a quantitative effect of the CYP2C19 and CYP2D6 genotypes on amitriptyline and nortriptyline pharmacokinetics. Production of nortriptyline from amitriptyline was associated with CYP2C19 genotypes, and clearance of amitriptyline through pathways other than biotransformation into nortriptyline was associated with CYP2D6 genotypes. These observations may be useful in developing individualized, optimal therapy with amitriptyline.

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Section: Discussionmentioning

confidence: 47%

Quantitative Modeling Analysis Demonstrates the Impact of CYP2C19 and CYP2D6 Genetic Polymorphisms on the Pharmacokinetics of Amitriptyline and Its Metabolite, Nortriptyline

Koh

Pak

Choi

et al. 2018

The Journal of Clinical Pharma

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“…administration. Several mechanisms have been proposed to explain this phenomenon, such as enterohepatic recycling, presence of absorption windows along the gastrointestinal tract, variations in the condition of the intestinal lumen pH and time-related fluctuations in gastric emptying (Godfrey et al, 2011). All these reasons, except enterohepatic cycling, are related to the absorption process.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics, biodistribution and bioavailability of isoliquiritigenin after intravenous and oral administration

Qiao

Zhang

Wang

et al. 2013

Pharmaceutical Biology

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Context: Isoliquiritigenin (ISL) has been shown to exhibit a variety of biological activities. However, there is little research on the pharmacokinetic behavior and tissues distribution of ISL. Objective: Pharmacokinetics, biodistribution and bioavailability of ISL after intravenous and oral administration were determined by systematic investigation in Sprague-Dawley rats. Materials and methods: ISL was dissolved in medicinal ethanol-Tween 80-0.9% sodium chloride saline in a volume ratio of 10:15:75. The ISL solution was injected in rats via a tail vein at a single dose of 10, 20 and 50 mg/kg and administered orally in rats at a single dose of 20, 50 and 100 mg/kg, respectively. Blood samples were collected at time intervals of 0.08, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 6, 8 and 12 h after intravenous injection. Tissues of interests in mice were collected immediately at each determined time point (0.5, 1, 2, 3 and 6 h) after cervical dislocation. Results: The dose-normalized AUC values were 7.3, 7.6 and 8.7 mg Â h/ml (calculated based on the dose of 10 mg/kg) for intravenous doses of 10, 20 and 50 mg/kg, respectively. The elimination half-lifes (t 1/2 ) were 4.9, 4.6 and 4.8 h at 10, 20 and 50 mg/kg intravenous doses, respectively. The F values were 29.86, 22.70, 33.62% for oral doses of 20, 50 and 100 mg/kg, respectively. Liver, heart and kidney were major distribution tissues of ISL in mice. The plasma protein binding of ISL in rats was 43.72%. Conclusion: The work may useful for further study of the bioactive mechanism of ISL.

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“…Therefore, gastric emptying may be a critical determining factor, and part of the danofloxacin could be delayed in the stomach, because chicken infected with E. coli , resulting in slow intestinal peristalsis and indigestion. In addition, the variability of absorption within different regions of the gut, and in our study, the absorption in infected chickens was really changed dramatically, and the absorption may be changed in different part of ileum and cecum (Godfrey, Arundel, Dong, & Bryant, ).…”

Section: Discussionmentioning

confidence: 47%

Population pharmacokinetics for danofloxacin in the intestinal contents of healthy and infected chickens

Tian

Chen

et al. 2019

Vet Pharm & Therapeutics

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Avian pathogenic Escherichia coli could cause localized and systemic infection in the poultry, and danofloxacin is usually used to treat avian colibacillosis through oral administration. To promote prudent use of danofloxacin and reduce the emergence of drug‐resistant E. coli strains, it is necessary to understand the population pharmacokinetics (PopPK) of danofloxacin in chicken intestines. In this study, reversed‐phase high performance liquid chromatography (HPLC) with fluorescence detection was used to detect the concentrations of danofloxacin in the contents of duodenum, jejunum, and ileum of the healthy and infected chickens after single oral administration (5 mg/kg body weight). Then, the PopPK of danofloxacin in intestines were analyzed using NONMEM software. As a result, a two‐compartment PK model best described the time‐concentration profile of duodenal, jejunal, and ileal contents. Interestingly, absorption rate (Ka), distribution volume (V), and clearance (CL) for danofloxacin from duodenal, jejunal to ileal contents were sequentially decreased in the healthy chickens. However, the trend of Ka, V, and CL of danofloxacin was changed dramatically in the intestine of infected chickens. Ka and V of danofloxacin in the jejunum were higher than in the ileum and duodenum. Compared with healthy chickens, Ka and V of danofloxacin in the duodenum decreased significantly, while increased in jejunum, respectively. It has been noted that Ka decreased and V increased in the ileum of infected chickens. Besides, CL in the duodenum, jejunum, and ileum of infected chickens was, respectively, lower than those of healthy chickens. Interestingly, the relative bioavailability (F) of danofloxacin in the ileum was relatively higher in both healthy and infected chickens. In addition, F in the duodenal, jejunal, and ileal contents of infected chickens was respectively higher than healthy chickens. In summary, the PopPK for danofloxacin in infected chicken intestines was quite different from healthy chickens. The absorption, distribution, and clearance of danofloxacin in healthy chickens decreased from duodenum to jejunum and to ileum. Moreover, the pharmacokinetic characteristics in the intestine of infected chickens changed significantly, and the pharmacokinetic characteristics in the ileum can be used as a representative of all intestinal segments.

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Modelling the Double Peak Phenomenon in pharmacokinetics

Cited by 66 publications

References 21 publications

Quantitative Modeling Analysis Demonstrates the Impact of CYP2C19 and CYP2D6 Genetic Polymorphisms on the Pharmacokinetics of Amitriptyline and Its Metabolite, Nortriptyline

Quantitative Modeling Analysis Demonstrates the Impact of CYP2C19 and CYP2D6 Genetic Polymorphisms on the Pharmacokinetics of Amitriptyline and Its Metabolite, Nortriptyline

Pharmacokinetics, biodistribution and bioavailability of isoliquiritigenin after intravenous and oral administration

Population pharmacokinetics for danofloxacin in the intestinal contents of healthy and infected chickens

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