Prediction of Drug Tissue to Plasma Concentration Ratios Using a Measured Volume of Distribution in Combination With Lipophilicity

Abstract Despite their importance in determining the dosing regimen of drugs in the clinic, only a few studies have investigated methods for predicting blood-to-plasma concentration ratios (Rb). This study established an Rb prediction model incorporating typical human pharmacokinetics (PK) parameters. Experimental Rb values were compiled for 289 compounds, offering reliable predictions by expanding the applicability domain. Notably, it is the largest list of Rb values reported so far. Subsequently, human PK parameters calculated from plasma drug concentrations, including the volume of distribution (Vd), clearance, mean residence time, and plasma protein binding rate, as well as 2702 kinds of molecular descriptors, were used to construct quantitative structure–PK relationship models for Rb. Among the evaluated PK parameters, logVd correlated best with Rb (correlation coefficient of 0.47). Thus, in addition to molecular descriptors selected by XGBoost, logVd was employed to construct the prediction models. Among the analyzed algorithms, artificial neural networks gave the best results. Following optimization using six molecular descriptors and logVd, the model exhibited a correlation coefficient of 0.64 and a root-mean-square error of 0.205, which were superior to those previously reported for other Rb prediction methods. Since Vd values and chemical structures are known for most medications, the Rb prediction model described herein is expected to be valuable in clinical settings. Graphical abstract

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Renal excretion of radiofluoride in the dog

American Journal of Physiology-Legacy Content ◽

10.1152/ajplegacy.1960.198.4.829 ◽

1960 ◽

Vol 198 (4) ◽

pp. 829-832 ◽

Cited By ~ 17

Author(s):

Curtis H. Carlson ◽

W. D. Armstrong ◽

Leon Singer ◽

Lerner B. Hinshaw

Keyword(s):

Plasma Concentration ◽

Glomerular Filtration ◽

Renal Excretion ◽

Urine Volume ◽

Urine Concentration ◽

Tubular Reabsorption ◽

Carrier Free ◽

Renal Clearances ◽

Concentration Ratios

Renal clearances of continuously infused radiofluoride were measured in 10 dogs in which a large part of the skeleton had been excluded from the system in order to produce a more constant plasma radiofluoride concentration. The results were evaluated to describe the factors of glomerular filtration and tubular reabsorption of fluoride under several conditions. The animals that received carrier-free radiofluoride infusions excreted urine with a mean radiofluoride concentration 3.4–14.5 times that of the plasma. The urine-to-plasma concentration ratios obtained with animals given a load of stable fluoride was 13.5–29.6. An increased urine volume resulted in a decreased tubular reabsorption of fluoride and the clearance was increased. Chlorothiazide increased radiofluoride excretion but decreased the urine concentration. The radiofluoride clearances were always less than the creatinine clearances but were 7.8–179 times the chloride clearances. The effect of chlorothiazide was to decrease the ratio of fluoride to chloride clearance by increasing chloride clearance more than fluoride clearance.

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Hyperthyroidism and the Dynamics of Distribution and Renal Excretion of Epinephrine in the Dog

American Journal of Physiology-Legacy Content ◽

10.1152/ajplegacy.1958.193.2.375 ◽

1958 ◽

Vol 193 (2) ◽

pp. 375-378 ◽

Cited By ~ 12

Author(s):

Richard T. Jones ◽

William D. Blake

Keyword(s):

Plasma Concentration ◽

Oral Administration ◽

Renal Excretion ◽

Volume Of Distribution ◽

Constant Infusion ◽

Thyroid Extract ◽

Anesthetized Dogs

Several parameters related to the dynamics of distribution and renal excretion of epinephrine were studied in anesthetized dogs before and during oral administration of thyroid extract. These parameters include: a) plasma concentration and renal excretion of epinephrine during constant infusion of l-epinephrine bitartrate, b) the rate of disappearance from plasma and volume of distribution of epinephrine, and c) the resting excretion of endogenous epinephrine before and during thyroid feeding. Except for an increase in the percentage of infused epinephrine excreted in the urine, there were essentially no changes in these parameters after feeding thyroid.

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Pharmacokinetics and metabolism of epidoxorubicin and doxorubicin in humans.

Journal of Clinical Oncology ◽

10.1200/jco.1988.6.3.517 ◽

1988 ◽

Vol 6 (3) ◽

pp. 517-526 ◽

Cited By ~ 127

Author(s):

K Mross ◽

P Maessen ◽

W J van der Vijgh ◽

H Gall ◽

E Boven ◽

...

Keyword(s):

Plasma Concentration ◽

Urinary Excretion ◽

Half Life ◽

Enterohepatic Circulation ◽

Plasma Concentrations ◽

Parent Drug ◽

Volume Of Distribution ◽

Maximum Plasma ◽

Cumulative Urinary Excretion ◽

Second Peak

Pharmacokinetics of doxorubicin (DOX), epidoxorubicin (EPI), and their metabolites in plasma have been performed in eight patients receiving 40 to 56 mg/m2 of both anthracyclines as a bolus injection in two sequential cycles. Terminal half-life and volume of distribution appeared to be smaller in case of EPI, whereas plasma clearance and cumulative urinary excretion was larger in comparison to DOX. The major metabolite of DOX was doxorubicinol (Aol) followed by 7-deoxy-doxorubicinol (7d-Aolon). Metabolism to glucuronides was found in case of EPI only. The area under the curves (AUC) of the metabolites of EPI decreased in the order of the glucoronides E-glu greater than Eol-glu, 7d-Aolon greater than epirubicinol (Eol). The AUC of Eol was half of the value in its counterpart Aol. In the case of EPI, the AUC of 7d-Aolon was twice the level of that of the corresponding metabolite of DOX. The terminal half-lives of the cytostatic metabolites Aol and Eol were similar, but longer than the corresponding values of their parent drugs. Half-lives of the glucuronides (E-glu, Eol-glu) were similar to the half-life of their parent drug. 7d-Aolon had a somewhat shorter half-life in comparison to both DOX and EPI. Approximately 6.2% of EPI and 5.9% of DOX were excreted by the kidney during the initial 48 hours. Aol was found in the urine of patients treated with DOX, whereas Eol, E-glu, and Eol-glu were detected in urine of patients treated with EPI. The cumulative urinary excretion appeared to be 10.5% for EPI and its metabolites, and 6.9% for DOX and its metabolite. The plasma concentration v time curves of (7d)-aglycones showed a second peak between two and 12 hours after injection, suggesting an enterohepatic circulation for metabolites lacking the daunosamine sugar moiety. The plasma concentrations of the glucuronides were maximal at 1.2 hours for E-glu and 1.9 hours for Eol-glu. All other compounds reached their maximum plasma concentration during the first minutes after the administration of DOX and EPI. Deviating plasma kinetics were observed in one patient, probably due to prior drug administration.

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A COMPARISON BETWEEN THE UPTAKES OF RADIOACTIVE PERCHLORATE AND IODIDE BY RAT AND GUINEA-PIG THYROID GLANDS

Journal of Endocrinology ◽

10.1677/joe.0.0450001 ◽

1969 ◽

Vol 45 (1) ◽

pp. 1-8 ◽

Cited By ~ 13

Author(s):

S. Y. CHOW ◽

L. R. CHANG ◽

M. S. YEN

Keyword(s):

Plasma Concentration ◽

Marked Effect ◽

Specific Activity ◽

Chronic Administration ◽

Anion Transport ◽

Thyroid Stimulating Hormone ◽

Thyroid Glands ◽

Stable Anion ◽

Dose Levels ◽

Concentration Ratios

SUMMARY Previous studies indicated that 36Cl-labelled perchlorate is concentrated by rat and rabbit thyroid gland. However, the extent of concentration of radioactive perchlorate in the gland was much less than that of iodide. Since perchlorate itself has a marked effect on anion transport in the thyroid and the specific activity of available [36C]perchlorate is very low, the stable anion as a carrier present in the injected radioactive perchlorate solution may affect the uptake of this radioactive compound by the gland. In this study, radioactive solutions of perchlorate and iodide containing different amounts of stable perchlorate or iodide (dosages ranged from 0·005 to 5 m-equiv./kg. body weight) were injected into groups of rats and guineapigs, and the thyroid: plasma concentration ratios of radioactive perchlorate and iodide were calculated and compared. These experiments were also repeated in animals pretreated with thyroid-stimulating hormone (TSH), after chronic administration of propylthiouracil (PTU), as well as in hypophysectomized animals. At the same dose levels of perchlorate, there was no difference in thyroid: plasma concentration ratios of radioactive perchlorate and iodide in control rats and guinea-pigs or in treated ones.

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The Role of Pharmacokinetics in Anaesthesia: Application to Intravenous Infusions

Anaesthesia and Intensive Care ◽

10.1177/0310057x8701500103 ◽

1987 ◽

Vol 15 (1) ◽

pp. 7-14 ◽

Cited By ~ 5

Author(s):

D. R. Stanski

Keyword(s):

Steady State ◽

Plasma Concentration ◽

Plasma Concentrations ◽

Pharmacokinetic Profile ◽

Volume Of Distribution ◽

Drug Dose ◽

Metabolic Clearance ◽

Drug Infusion ◽

Fixed Rate ◽

Elimination Half

Pharmacokinetic concepts describe the relationship between drug dose and resulting plasma concentration. A drug's pharmacokinetic profile can be described by distribution and elimination half-lives, initial volume of distribution, steady-state distribution volume, and metabolic and distributional clearance. After initiating a fixed rate of drug infusion, four to five terminal elimination half-lives are required to reach a steady state of constant plasma concentration. If a loading dose is given, a steady state can be achieved more rapidly. The most rapid method of achieving a constant plasma concentration involves using a variable rate of drug infusion that adjusts for the metabolic clearance and distribution of the drug. Computer-driven infusion pumps can be used to rapidly achieve, then maintain, constant plasma concentrations of a drug.

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