scholarly journals Interrelationships in rats of tissue pools of cholecalciferol and 25-hydroxycholecalciferol formed in u.v. light

1986 ◽  
Vol 233 (2) ◽  
pp. 535-540 ◽  
Author(s):  
D E M Lawson ◽  
S H Sedrani ◽  
J Douglas
Keyword(s):  
Vitamin D ◽  
Adipose Tissue ◽  
Compartment Model ◽  
Volume Of Distribution ◽  
High Rate ◽  
Pharmacokinetic Analysis ◽  
Rat Skin ◽  
Small Rise ◽  
Rat Adipose Tissue ◽  
25 Hydroxycholecalciferol

Vitamin D-deficient rats were irradiated with u.v. light three times weekly for 30 min for several weeks. D3 (cholecalciferol) and 25(OH)D3 (25-hydroxycholecalciferol) concentrations in skin, plasma, muscle and adipose tissue were measured. In other experiments, isolated skin or the whole animal was irradiated once and the cholecalciferol response monitored. Only a small fraction of the 7-dehydrocholesterol in skin is converted into D3 (less than 2%), and the presence of fur decreases the proportion converted into 20% of that occurring in shaved rat skin. D3 formed in the skin disappears relatively slowly, so that about 90% has gone after 7 days. In normal rats 10 micrograms of D3 formed over 2 h irradiation only caused a small rise in plasma D3 concentration over the following week, indicative of a high rate of clearance from this tissue. Irradiation of vitamin D-deficient rats for a prolonged period raised plasma D3 and 25(OH)D3 concentrations to a constant value. D3, but not 25(OH)D3, could be found in adipose tissue and muscle. Prolonged irradiation of normal rats showed these tissues and plasma could hold very large amounts of D3. Pharmacokinetic analysis of the changes in D3 concentration in rats showed that the disposition kinetics of D3 was explained by a two-compartment model with half-lives of 13.8 and 7.7 days. The volume of distribution of the more-slowly-turning-over compartment was 500 ml, which presumably reflects the large amounts of D3 that can accumulate in adipose tissue. Rat skin can synthesize about 0.85 ng of D3/mJ of u.v. light energy, but it seems that not all this is available to the rat. Adipose-tissue D3 is available for use by the rat, the t1/2 being 12.0 days.

scholarly journals Population Pharmacokinetics Modelling and Simulation of Mitotane in Patients with Adrenocortical Carcinoma: An Individualized Dose Regimen to Target All Patients at Three Months?

Pharmaceutics ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 566 ◽  
Author(s):  
Yoann Cazaubon ◽  
Yohann Talineau ◽  
Catherine Feliu ◽  
Céline Konecki ◽  
Jennifer Russello ◽  
...  
Keyword(s):  
Adrenocortical Carcinoma ◽  
Plasma Concentrations ◽  
Therapeutic Index ◽  
Compartment Model ◽  
Volume Of Distribution ◽  
Pharmacokinetic Analysis ◽  
Concentration Data ◽  
Starting Dose ◽  
Dosing Regimens ◽  
Data Files

Mitotane is the most effective agent in post-operative treatment of adrenocortical carcinoma. In adults, the starting dose is 2–3 g/day and should be slightly increased to reach the therapeutic index of 14–20 mg/L. This study developed a population PK model for mitotane and to simulate recommended/high dosing regimens. We retrospectively analyzed the data files of 38 patients with 503 plasma concentrations for the pharmacokinetic analysis. Monolix version 2019R1 was used for non-linear mixed-effects modelling. Monte Carlo simulations were performed to evaluate the probability of target attainment (PTA ≥ 14 mg/L) at one month and at three months. Mitotane concentration data were best described by a linear one-compartment model. The estimated PK parameters (between-subject variability) were: 8900 L (90.4%) for central volume of distribution (V) and 70 L·h−1 (29.3%) for clearance (Cl). HDL, Triglyceride (Tg) and a latent covariate were found to influence Cl. The PTA at three months for 3, 6, 9, and 12 g per day was 10%, 55%, 76%, and 85%, respectively. For a loading dose of 15 g/day for one month then 5 g/day, the PTA in the first and third months was 57 and 69%, respectively. This is the first PKpop model of mitotane highlighting the effect of HDL and Tg covariates on the clearance as well as a subpopulation of ultrafast metabolizer. The simulations suggest that recommended dose regimens are not enough to target the therapeutic threshold in the third month.

scholarly journals A Population Pharmacokinetic Analysis Shows that Arylacetamide Deacetylase (AADAC) Gene Polymorphism and HIV Infection Affect the Exposure of Rifapentine

2019 ◽  
Vol 63 (4) ◽  
Author(s):  
Jose Francis ◽  
Simbarashe P. Zvada ◽  
Paolo Denti ◽  
Mark Hatherill ◽  
Salome Charalambous ◽  
...  
Keyword(s):  
Food Intake ◽  
Hiv Infection ◽  
Pregnane X Receptor ◽  
Compartment Model ◽  
Population Pharmacokinetic Analysis ◽  
Volume Of Distribution ◽  
Fat Free Mass ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Antituberculosis Treatment

ABSTRACT Rifapentine is a rifamycin used to treat tuberculosis. As is the case for rifampin, plasma exposures of rifapentine are associated with the treatment response. While concomitant food intake and HIV infection explain part of the pharmacokinetic variability associated with rifapentine, few studies have evaluated the contribution of genetic polymorphisms. We evaluated the effects of functionally significant polymorphisms of the genes encoding OATP1B1, the pregnane X receptor (PXR), constitutive androstane (CAR), and arylacetamide deacetylase (AADAC) on rifapentine exposure. Two studies evaluating novel regimens among southern African patients with drug-susceptible pulmonary tuberculosis were included in this analysis. In the RIFAQUIN study, rifapentine was administered in the continuation phase of antituberculosis treatment in 1,200-mg-once-weekly or 900-mg-twice-weekly doses. In the Daily RPE study, 450 or 600 mg was given daily during the intensive phase of treatment. Nonlinear mixed-effects modeling was used to describe the pharmacokinetics of rifapentine and to identify significant covariates. A total of 1,144 drug concentration measurements from 326 patients were included in the analysis. Pharmacogenetic information was available for 162 patients. A one-compartment model with first-order elimination and transit compartment absorption described the data well. In a typical patient (body weight, 56 kg; fat-free mass, 45 kg), the values of clearance and volume of distribution were 1.33 liters/h and 25 liters, respectively. Patients carrying the AA variant (65.4%) of AADAC rs1803155 were found to have a 10.4% lower clearance. HIV-infected patients had a 21.9% lower bioavailability. Once-weekly doses of 1,200 mg were associated with a reduced clearance (13.2%) compared to that achieved with more frequently administered doses. Bioavailability was 23.3% lower among patients participating in the Daily RPE study than in those participating in the RIFAQUIN study. This is the first study to report the effect of AADAC rs1803155AA on rifapentine clearance. The observed increase in exposure is modest and unlikely to be of clinical relevance. The difference in bioavailability between the two studies is probably related to the differences in food intake concomitant with the dose. HIV-coinfected patients had lower rifapentine exposures.

scholarly journals Compartmental Pharmacokinetic Analysis of Oral Amprenavir with Secondary Peaks

2007 ◽  
Vol 51 (5) ◽  
pp. 1822-1826 ◽  
Author(s):  
Olanrewaju Okusanya ◽  
Alan Forrest ◽  
Robin DiFrancesco ◽  
Sanela Bilic ◽  
Susan Rosenkranz ◽  
...  
Keyword(s):  
Plasma Concentrations ◽  
Compartment Model ◽  
Central Compartment ◽  
Volume Of Distribution ◽  
Information Criteria ◽  
Secondary Peak ◽  
Pharmacokinetic Analysis ◽  
Therapeutic Drug ◽  
Healthy Human ◽  
Two Compartment Model

ABSTRACT Amprenavir is a protease inhibitor that has been shown to have secondary peaks postulated to be due to enterohepatic recycling. We propose a model to describe the pharmacokinetics of amprenavir which accommodates the secondary peak(s). A total of 82 healthy human immunodeficiency virus (HIV)-seronegative subjects were administered a single 600-mg dose of amprenavir as part of adult AIDS Clinical Trials Group protocol A5043. Serial blood samples were obtained over 24 h. Samples were analyzed for amprenavir and fit to a compartmental model using ADAPT II software, with all relevant parameters conditional with respect to bioavailability. The model accommodated secondary peaks by incorporating clearance out of the central compartment with delayed instantaneous release back into the gut compartment. The data were weighted by the inverse of the estimated measurement error variance; model discrimination was determined using Akaike's Information Criteria. A total of 76 subjects were evaluable in the study analysis. The data were best fit by a two-compartment model, with 98.7% of the subjects demonstrating a secondary peak. Amprenavir had a mean total clearance of 1.163 liters/h/kg of body weight (0.7), a central volume of distribution of 1.208 liters/kg (0.8), a peripheral volume of distribution of 8.2 liters/kg (0.81), and distributional clearance of 0.04 liters/h/kg (0.81). The time to the secondary peak was 7.86 h (0.17), and clearance into a recycling compartment was 0.111 liters/kg/h (0.74). Amprenavir pharmacokinetics has been well described using a two-compartment model with clearance to a recycling compartment and release back into the gut. The nature of the secondary peaks may be an important consideration for the interpretation of amprenavir plasma concentrations during therapeutic drug monitoring.

scholarly journals Rat adipose tissue rapidly accumulates and slowly releases an orally-administered high vitamin D dose

1998 ◽  
Vol 79 (6) ◽  
pp. 527-532 ◽  
Author(s):  
D. A. Janneke Brouwer ◽  
Jackelieng Van Beek ◽  
Harri Ferwerda ◽  
Astrid M. Brugman ◽  
Fiona R. M. van der Klis ◽  
...  
Keyword(s):  
Vitamin D ◽  
Adipose Tissue ◽  
Dietary Vitamin ◽  
High Dose ◽  
Hydroxyvitamin D ◽  
Female Wistar Rats ◽  
25 Hydroxyvitamin D ◽  
Wet Weight ◽  
Rat Adipose Tissue ◽  
Subcutaneous Adipose

We investigated the effect of oral high-dose cholecalciferol on plasma and adipose tissue cholecalciferol and its subsequent release, and on plasma 25-hydroxyvitamin D (25(OH)D). Female Wistar rats (n 126) received 37·5 μg cholecalciferol/d for 14 d and were subsequently studied for a further 88 d. Two subgroups of eighteen rats each were fasted for 3 d immediately after treatment (days 14−17) and at the end of the study (days 98−101). During treatment, plasma cholecalciferol increased rapidly to reach a steady-state. Plasma 25(OH)D and adipose tissue cholecalciferol increased linearly for 1 - 2 d after treatment. Serum Ca and inorganic phosphate also increased. Subsequently half-lives of plasma cholecalciferol and 25(OH)D, and perirenal and subcutaneous adipose tissue were: 1·4, 22·5, 97·5 and 80·9 d respectively. Fasting, as compared with ad libitum feeding, caused increased plasma free fatty acids, weight loss up to 14% and increased adipose tissue cholecalciferol (nmol/g wet weight). It did not affect plasma cholecalciferol immediately after cholecalciferol treatment, but raised plasma 25(OH)D. Fasting at the end of the study decreased plasma cholecalciferol and increased plasma 25(OH)D. We conclude that orally-administered cholecalciferol rapidly accumulates in adipose tissue and that it is very slowly released while there is energy balance. Fasting causes preferential loss of triacylglycerols from adipose tissue, as opposed to cholecalciferol, but nevertheless augments plasma 25(OH)D. Adipose tissue may act as a ‘buffer to functional vitamin D status’ by preventing, to a certain extent, unregulated production of 25(OH)D from dietary vitamin D, and by slowly releasing vitamin D under fasting conditions.

scholarly journals Population Pharmacokinetics of Diazoxide in Children with Hyperinsulinemic Hypoglycemia

2017 ◽  
Vol 88 (5) ◽  
pp. 316-323 ◽  
Author(s):  
Rika Kizu ◽  
Kazuko Nishimura ◽  
Reiko Sato ◽  
Kenjiro Kosaki ◽  
Toshiaki Tanaka ◽  
...  
Keyword(s):  
Drug Exposure ◽  
Compartment Model ◽  
Population Pharmacokinetic Analysis ◽  
Volume Of Distribution ◽  
The Body ◽  
Pharmacokinetic Analysis ◽  
Hyperinsulinemic Hypoglycemia ◽  
Population Pharmacokinetic ◽  
Nonlinear Mixed Effects Model ◽  
First Time

Background: Diazoxide is the first-line treatment for pediatric hyperinsulinemic hypoglycemia (HI). This study aimed to elucidate the pharmacokinetics of diazoxide in children with HI. Methods: We obtained 81 blood samples from 22 children with HI. Measured serum diazoxide concentrations were used for population pharmacokinetic analysis. Patient factors influencing pharmacokinetics were estimated using nonlinear mixed-effects model analysis. Relationships between drug exposure and adverse drug reactions were also investigated. Results: Diazoxide disposition in the body was described by a 1-compartment model. Oral clearance (CL/F) and the volume of distribution were proportional to body weight (WT), as expressed by CL/F in males (liters/h) = 0.0358 + 0.00374 × WT (kg). CL/F in females was 39% greater than that in males. Steady-state concentrations of diazoxide were similar following twice- and 3 times-daily dosing when the total daily doses were comparable. A patient whose serum diazoxide concentration exceeded 100 μg/mL over a 4-month period developed hyperglycemia. No significant correlation was observed between severity of hirsutism and diazoxide concentration. Conclusion: We have proposed for the first time a population pharmacokinetic model for diazoxide in children with HI. The potential risk of diabetes mellitus and/or hyperglycemia increases when serum concentrations of diazoxide exceed 100 μg/mL.

POPULATION PHARMACOKINETICS OF INTRAVENOUS ALBUTEROL IN CHILDREN WITH STATUS ASTHMATICUS

2015 ◽  
Vol 101 (1) ◽  
pp. e1.31-e1
Author(s):  
Nienke J Vet ◽  
Brenda CM de Winter ◽  
Saskia N de Wildt ◽  
Bart CH van der Nagel ◽  
Catherijne AJ Knibbe ◽  
...  
Keyword(s):  
Population Pharmacokinetics ◽  
Status Asthmaticus ◽  
Clinical Symptoms ◽  
Compartment Model ◽  
Population Pharmacokinetic Analysis ◽  
Volume Of Distribution ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Creatinine Concentration ◽  
Central Volume

ObjectivesTo develop a population pharmacokinetic model of R-albuterol and S-albuterol for children suffering from status asthmaticus following continuous intravenous administration.MethodsAt the pediatric ICU 19 children suffering from severe status asthmaticus were treated using continuous intravenous albuterol in doses based on clinical symptoms (range 0.1–10 µg/kg/min). During therapy 111 blood samples were collected and analysed for R- and S-albuterol using a validated LC/MS-MS method. A population pharmacokinetic analysis was conducted using non-linear mixed effects modelling (NONMEM 7.2). Data was logarithmically transformed. Model selection criteria were decrease in objective function, diagnostic plots and NPDE. The covariates (range) analysed were bodyweight (7.8–70 kg), age (0.8–15.3 years), creatinine concentration (17–70 µmol/L), alanine transaminase (5–29 IU/L), and urea (1.6–4.8 mmol/L).ResultsA two-compartment model with separated clearance for R- (16.3 L/h) and S-albuterol (8.8 L/h) best described the data. Separated values for central volume of distribution (12.9 L), peripheral volume of distribution (45.2 L) and intercompartmental clearance (20.0 L/h) did not improve the model. Between-subject variability was described for clearance of R-albuterol (42%), clearance of S-albuterol (37%) and central volume of distribution (280%). Weight is a significant covariate using a power function. The exponent of the powerfunction was fixed at 0.75 for clearance and intercompartmental and at 1 for central and peripheral volume of distribution. Estimation of the exponent resulted in similar values and did not improve the model. No other covariates were identified.ConclusionThe population pharmacokinetics of R- and S-albuterol are described. This model can be used to evaluate the correlation between albuterol pharmacokinetics and effect in a population pharmacokinetic-pharmacodynamic analysis.

scholarly journals Metabolism of vitamin D. A new cholecalciferol metabolite, involving loss of hydrogen at C-1, in chick intestinal nuclei

1969 ◽  
Vol 115 (2) ◽  
pp. 269-277 ◽  
Author(s):  
D. E. M. Lawson ◽  
P. W. Wilson ◽  
E. Kodicek
Keyword(s):  
Vitamin D ◽  
Adipose Tissue ◽  
Maximum Concentration ◽  
Simultaneous Administration ◽  
Polar Material ◽  
Polar Metabolite ◽  
Chemical Structures ◽  
Intracellular Organelle ◽  
Liver And Kidney ◽  
25 Hydroxycholecalciferol

1. A comparison was made of the nature and intestinal intracellular distribution of the metabolites formed in vitamin D-deficient chicks from [4−14C]cholecalciferol and [1−3H]cholecalciferol. 2. The simultaneous administration of the two radioactive substances showed the presence in blood, liver, intestine, kidney and bone of cholecalciferol, its ester, 25-hydroxycholecalciferol and a further metabolite of cholecalciferol more polar than 25-hydroxycholecalciferol. The 3H/14C ratios in these four radioactive components were the same as that of the dosed material (4·7:1) with the exception of the most polar material. The 3H/14C ratio was lower in the fourth, most polar, metabolite (0·4:1–1·8:1) in all tissues examined, with the exception of blood. 3. In the chick intestine the polar metabolite accounted for almost 70% of the radioactivity in this tissue after a dose of 0·5μg. of [4−14C,1−3H]cholecalciferol. This polar metabolite from the intestine also had the lowest 3H/14C ratio of all the tissues. It appears that in the chick intestine the polar metabolite reaches a maximum concentration of 1ng./g. of tissue, above which it cannot be increased irrespective of the dose of the vitamin. 4. The intestinal intracellular organelle with the highest concentration of 14C radioactivity is the nucleus, and this radioactivity is almost entirely due to the polar metabolite with the lowered 3H/14C ratio, in this case <0·2:1. It appears to be further localized in the chromatin of the nuclei. However, about half of the polar metabolite in the intestine is extranuclear. 5. Double-labelled 25-hydroxycholecalciferol was prepared and after its administration to vitamin D-deficient chicks the polar metabolite with the lowered 3H/14C ratio was detected in liver, kidney, intestine, bone, muscle and heart. 6. None of the polar metabolite with the lowered 3H/14C ratio was detected 16hr. after dosing with either the double-labelled vitamin or the double-labelled 25-hydroxycholecalciferol in blood and adipose tissue of vitamin D-deficient chicks, nor in the intestine, liver and kidney of supplemented birds. 7. The reasons for this loss of 3H relative to 14C are discussed in relation to possible chemical structures of this new polar metabolite.

Insulin Sensitizing Effects of Vitamin D Mediated through Reduced Adipose Tissue Inflammation and Fibrosis

Diabetes ◽  
2018 ◽  
Vol 67 (Supplement 1) ◽  
pp. 39-OR
Author(s):  
ERIC LONTCHI-YIMAGOU ◽  
SONA KANG ◽  
KEHAO ZHANG ◽  
AKANKASHA GOYAL ◽  
JEE YOUNG YOU ◽  
...  
Keyword(s):  
Vitamin D ◽  
Adipose Tissue ◽  
Adipose Tissue Inflammation ◽  
Tissue Inflammation
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