New Perspectives in Clinical Pharmacokinetics-1: the Importance of Updating the Teaching in Pharmacokinetics that both Clearance and Elimination Rate Constant Approaches Are Mathematically Proven Equally Valid

2018 ◽  
Vol 20 (2) ◽  
Author(s):  
Roger Jelliffe ◽  
David Bayard
Keyword(s):  
Rate Constant ◽  
Elimination Rate ◽  
Elimination Rate Constant ◽  
Clinical Pharmacokinetics

Semiparametric approach to pharmacokinetic-pharmacodynamic data

1989 ◽  
Vol 256 (4) ◽  
pp. R1005-R1010
Author(s):  
D. Verotta ◽  
S. L. Beal ◽  
L. B. Sheiner
Keyword(s):  
Steady State ◽  
Rate Constant ◽  
Drug Concentration ◽  
Venous Blood ◽  
Time Lag ◽  
Elimination Rate ◽  
Hysteresis Loops ◽  
Real Data ◽  
Elimination Rate Constant ◽  
Arterial Blood

A semiparametric model for analysis of pharmacokinetic (PK) and pharmacodynamic (PD) data arising from non-steady-state experiments is presented. The model describes time lag between drug concentration in a sampling compartment, e.g., venous blood (Cv), and drug effect (E). If drug concentration at the effect site (Ce) equilibrates with arterial blood concentration (Ca) slower than with Cv, a non-steady-state experiment yields E vs. Cv data describing a counterclockwise hysteresis loop. If Ce equilibrates with Ca faster than with Cv, clockwise hysteresis is observed. To model hysteresis, a parametric model is proposed linking (unobserved) Ca to Cv with elimination rate constant kappa ov and also linking Ca to Ce with elimination rate constant kappa oe. When kappa oe is greater than (or less than) kappa ov clockwise (or counterclockwise) hysteresis occurs. Given kappa oe and kappa ov, numerical (constrained) deconvolution is used to obtain the disposition function of the arterial compartment (Ha), and convolution is used to calculate Ce given Ha. The values of kappa oe and kappa ov are chosen to collapse the hysteresis loops to single curves representing the Ce-E (steady-state) concentration-response curve. Simulations, and an application to real data, are reported.

scholarly journals Pharmacokinetics of human chorionic gonadotropin after i.m. administration in goats (Capra hircus)

Reproduction ◽  
2012 ◽  
Vol 144 (1) ◽  
pp. 77-81 ◽  
Author(s):  
M Saleh ◽  
M Shahin ◽  
W Wuttke ◽  
M Gauly ◽  
W Holtz
Keyword(s):  
Rate Constant ◽  
Chorionic Gonadotropin ◽  
Human Chorionic Gonadotropin ◽  
Half Life ◽  
Absorption Rate ◽  
Elimination Rate ◽  
Elimination Rate Constant ◽  
Capra Hircus ◽  
Absorption Rate Constant ◽  
Biological Half Life

The present investigation addresses the pharmacokinetics of human chorionic gonadotropin (hCG), intramuscularly (i.m.) administered to goats. Nine pluriparous does of the Boer goat breed, 2–6 years of age and weighing 45–60 kg, were administered 500 IU hCG (2 ml Chorulon) deep into the thigh musculature 18 h after superovulatory FSH treatment. Blood samples were drawn from the jugular vein at 2 h intervals for the first 24 h, at 6 h intervals until 42 h, and at 12 h intervals until 114 h after administration. After centrifugation, plasma hCG concentrations were determined by electrochemiluminescence immunoassay. Pharmacokinetical parameters were as follows: lag time, 0.4 (s.e.m. 0.1) h; absorption rate constant, 0.34 (s.e.m. 0.002) h; absorption half-life, 2.7 (s.e.m. 0.5) h; elimination rate constant, 0.02 (s.e.m. 0.002) h; biological half-life, 39.4 (s.e.m. 5.1) h; and apparent volume of distribution, 16.9 (s.e.m. 4.3) l. The plasma hCG profile was characterized by an absorption phase of 11.6 (s.e.m. 1.8) h and an elimination phase of 70.0 (s.e.m. 9.8) h, with considerable individual variation in bioavailability and pharmacokinetical parameters. Biological half-life was negatively correlated (P<0.05) with peak concentration (r=−0.76), absorption rate constant (r=−0.78), and elimination rate constant (r=−0.87). The results indicate that after rapid absorption, hCG remains in the circulation for an extended period. This has to be taken into account when assessing the stimulatory response to hCG treatment on an ovarian level.

Cefamandole Distribution in Serum, Adipose Tissue, and Wound Drainage in Morbidly Obese Patients

1986 ◽  
Vol 20 (11) ◽  
pp. 869-873 ◽  
Author(s):  
Henry J. Mann ◽  
Henry Buchwald
Keyword(s):  
Adipose Tissue ◽  
Rate Constant ◽  
Subcutaneous Adipose Tissue ◽  
Elimination Rate ◽  
Elimination Rate Constant ◽  
Morbidly Obese ◽  
Obese Patients ◽  
Tissue Concentrations ◽  
Wound Drainage ◽  
Subcutaneous Adipose

Distribution and elimination of cefamandole 2 g iv were studied in 11 morbidly obese patients during a gastric bypass operation and again on the first postoperative day. Serum, subcutaneous adipose tissue, wound drainage, and urine were analyzed by high performance liquid chromatography for cefamandole and pharmacokinetic parameters from the intraoperative period were compared to those obtained postoperatively. Total body clearance was significantly greater (p < 0.001) postoperatively (297 ml/min) than intraoperatively (254 ml/min). Volume changes were unpredictable but the elimination rate constant tended to increase postoperatively. Renal clearance and percentage of urinary recovery were significantly increased (p < 0.01) postoperatively. The patients had a mean (± SD) volume of the central compartment of 10.3 (± 2.3) L, volume at steady state of 18.3 (± 3.9) L, and elimination rate constant of 1.67 (± 0.63) h−1. Tissue concentrations of cefamandole were highest during the first hour after drug administration and were < 1 μg/g after 3.5 hours. Mean wound drainage concentrations ranged between 10 and 12 μg/ml during a dosing interval and dropped to 7 μg/ml 12 hours after the last dose. Intraoperative dosing of cefamandole is required to maintain subcutaneous adipose tissue concentrations > 1 μg/g during procedures longer than three hours in morbidly obese patients. A postoperative dose of cefamandole 2 g iv q6h will provide sustained and therapeutic concentrations in the wound drainage of morbidly obese patients.

scholarly journals Kinetic simulation method of C-reactive protein in beagle dogs during acute inflammation

2017 ◽  
Vol 15 (2) ◽  
pp. 120-123
Author(s):  
Takashi Kuribayashi
Keyword(s):  
Rate Constant ◽  
Inflammatory Responses ◽  
Elimination Rate ◽  
Simulation Method ◽  
Elimination Rate Constant ◽  
Enzyme Linked Immunosorbent Assay ◽  
Serum Concentrations ◽  
Beagle Dogs ◽  
C Reactive Protein ◽  
Reactive Protein

The half-life ( t1/2) of C-reactive protein (CRP) and its ability to stimulate weak inflammatory responses were investigated in beagle dogs. Four beagle dogs were administered 20 mg/kg indomethacin and blood was collected from the cephalic vein pre-dosing and at 24, 48, 72, 96, 144, 192, 240, 312, and 360 h post-administration. The serum concentrations of CRP were measured by enzyme-linked immunosorbent assay. The serum t1/2 was calculated using the equation 0.693/elimination rate constant. The serum concentration of CRP beyond 192 h post-administration declined to levels in the normal range. The t1/2 was 148.3 h, which is considered to be the essential t1/2 of CRP. The simulation of CRP serum concentrations at arbitrary times using the elimination rate constant obtained in this study became possible.

Elimination Rate Constant Describing Clearance of Infused Fluid from Plasma Is Independent of Large Infusion Volumes of 0.9% Saline in Sheep

2004 ◽  
Vol 101 (3) ◽  
pp. 666-674 ◽  
Author(s):  
Christer H. Svensén ◽  
Kirk P. Brauer ◽  
Robert G. Hahn ◽  
Tatsuo Uchida ◽  
Lillian D. Traber ◽  
...  
Keyword(s):  
Rate Constant ◽  
Saline Solution ◽  
Renal Excretion ◽  
Elimination Rate ◽  
Repeated Measurements ◽  
Elimination Rate Constant ◽  
Urinary Output ◽  
Time Curve ◽  
Crystalloid Infusion ◽  
Arterial Plasma

Background The purpose of this study was to determine the influence of varying large crystalloid infusion volumes, ranging from a volume that has been safely administered to volunteers to a volume that greatly exceeds a practical volume for studies in normovolemic humans, of rapidly infused 0.9% saline on the elimination rate constant in sheep. Methods Six sheep underwent three randomly ordered, 20 min, intravenous infusions of 0.9% saline in volumes of 25 ml/kg, 50 ml/kg and 100 ml/kg. Repeated measurements of arterial plasma dilution were analyzed using the volume kinetic approach to determine the apparent volumes of the central (V1) and peripheral (V2) body fluid spaces, the elimination rate constant (kr) describing clearance from the central fluid space and the rate constant (kt) for the diffusion of fluid between the central and the peripheral fluid spaces. The latter constant was split in to two constants, one describing flow out from the central fluid space and one describing flow into the central fluid space. Urinary output was measured in all sheep. Results kr was comparable at each infused volume (38.3 +/- 4.5, 32.2 +/- 4.2, and 36.7 +/- 7.0 ml/min, respectively, in the 25 ml/kg, 50 ml/kg, and 100 ml/kg protocols). However, for the largest infusion, other kinetic parameters were influenced by the magnitude of the infusion. V2 was significantly increased (P &lt; 0.05) and the area under the dilution-time curve divided by the infused volume was 20% lower for the largest infusion (P &lt; 0.03). Although urinary output increased as the infusion volume increased, only 59% of the administered volume had been excreted at 180 min after the 100 ml/kg infusion as compared with approximately 90% after the other two infusions (P &lt; 0.01). Conclusions Elimination from the central fluid space of large, rapidly infused volumes of saline solution is independent of infused volume. Larger volumes are apparently cleared from the central fluid space (V1) by expansion of a peripheral volume (V2) as renal excretion fails to increase in proportion to the volume of infused fluid.

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