Pharmacokinetics and organ metabolism of carboxyamidated and glycine-extended gastrins in pigs

1996 ◽  
Vol 271 (1) ◽  
pp. G156-G163 ◽  
Author(s):  
C. P. Hansen ◽  
F. Stadil ◽  
L. Yucun ◽  
J. F. Rehfeld
Keyword(s):  
Clearance Rate ◽  
Apparent Volume ◽  
Volume Of Distribution ◽  
Metabolic Clearance ◽  
Metabolic Clearance Rate ◽  
Constant Rate Infusion ◽  
Constant Rate ◽  
Vascular Beds ◽  
Apparent Volume Of Distribution ◽  
Rate Infusion

The elimination of carboxyamidated gastrin-17 and its glycine-extended precursor was studied in anesthetized pigs during constant-rate infusion. Extraction of amidated gastrin-17 was recorded in the hindlimb (42%), kidney (40%), head (32%, P < 0.001), and the gut (13%, P < 0.01). Elimination was not recorded in the liver, lungs, or heart. Extraction of glycine-extended gastrin-17 was measured in the kidney (36%), hindlimb (31%, P < 0.001), head (26%), and the gut (16%, P < 0.01), but not in the liver or the lungs. Glycine-extended gastrin-17 was not processed to amidated gastrin during infusion. The half-life, metabolic clearance rate, and apparent volume of distribution for amidated gastrin-17 were 3.5 +/- 0.4 min, 15.5 +/- 1.1 ml.kg-1.min-1, and 76.5 +/- 9.9 ml/kg, respectively, and for glycine-extended gastrin-17 were 4.3 +/- 0.6 min, 17.4 +/- 0.9 ml.kg-1.min-1, and 104.7 +/- 11.9 ml/kg, respectively. We conclude that extraction of amidated and glycine-extended gastrin-17 varies in the vascular beds, with elimination mainly confined to nonorgan tissues and the kidneys.

The metabolism of gastrin-52 and gastrin-6 in pigs

2000 ◽  
Vol 279 (3) ◽  
pp. G552-G560 ◽  
Author(s):  
C. Palnæs Hansen ◽  
J. P. Goetze ◽  
F. Stadil ◽  
J. F. Rehfeld
Keyword(s):  
Clearance Rate ◽  
Half Life ◽  
Bolus Injection ◽  
Apparent Volume ◽  
Volume Of Distribution ◽  
Metabolic Clearance ◽  
Metabolic Clearance Rate ◽  
Organ Specific ◽  
Differential Elimination ◽  
Apparent Volume Of Distribution

The kinetics and metabolism in various organs of three bioactive products of progastrin, the small sulfated and nonsulfated gastrin-6 and the large nonsulfated gastrin-52, were examined during intravenous administration in anesthetized pigs. The kidney, hindlimb, liver, head, and gut eliminated the hexapeptides efficiently, with a fractional extraction ranging from 0.50 to 0.28 ( P < 0.001–0.05). No metabolism was recorded in the lungs, and sulfation was without influence on the extraction of gastrin-6. Gastrin-52 was eliminated only in the kidney and the head, with a fractional extraction between 0.23 and 0.11 ( P < 0.01–0.05). The half-life of sulfated and nonsulfated gastrin-6 was 1.5 ± 0.4 and 1.4 ± 0.3 min, the metabolic clearance rate (MCR) was 80.8 ± 7.6 and 116.0 ± 13.5 ml · kg−1· min−1( P < 0.05), and the apparent volume of distribution (Vdss) was 199.3 ± 70.1 and 231.4 ± 37.3 ml/kg, respectively. The decay of gastrin-52 in plasma was biexponential. The half-lives of this biexponential after a bolus injection were 3.9 ± 0.5 ( T1/2α) and 25.7 ± 1.4 ( T1/2β) min, and the MCR and Vdsswere 4.2 ± 0.4 ml · kg−1· min−1and 116.2 ± 16.2 ml/kg1. We conclude that there is a differential elimination of progastrin products in splanchnic and nonsplanchnic tissue, which depends on the chain length of the peptides. Sulfation of gastrin-6 had no influence on the organ-specific extraction but reduced the MCR. Our results are in keeping with previous studies of nonsulfated gastrin-17, which is extracted in the kidney, head, limb, and gut but not in the liver.

Metabolism and acid secretory effect of sulfated and nonsulfated gastrin-6 in humans

2000 ◽  
Vol 279 (5) ◽  
pp. G903-G909 ◽  
Author(s):  
C. Palnæs Hansen ◽  
F. Stadil ◽  
J. F. Rehfeld
Keyword(s):  
Clearance Rate ◽  
Main Product ◽  
Acid Output ◽  
Normal Subjects ◽  
Apparent Volume ◽  
Volume Of Distribution ◽  
Pharmacokinetic Parameters ◽  
Metabolic Clearance ◽  
Metabolic Clearance Rate ◽  
Apparent Volume Of Distribution

The antral hormone gastrin is synthesized by processing progastrin into different peptides that stimulate gastric secretion. The effect on acid secretion depends mainly on the metabolic clearance rate of the peptides, but some of them may differ in potency and maximum acid output at similar concentrations in plasma. Sulfated and nonsulfated gastrin-6 are the smallest circulating bioactive gastrins in humans. Their effect and metabolism have now been investigated in nine normal subjects and compared with nonsulfated gastrin-17, a main product of progastrin. Maximum acid output after stimulation with gastrin-17, sulfated gastrin-6, and nonsulfated gastrin-6 were 28.3 ± 2.0, 24.5 ± 2.0 ( P < 0.02), and 19.3 ± 2.3 ( P < 0.05) mmol H+/50 min, respectively, and the corresponding EC50values were 43 ± 6, 24 ± 2 ( P < 0.01), and 25 ± 2 (not significant) pmol/l. The half-life of gastrin-17 was 5.3 ± 0.3 min, the metabolic clearance rate (MCR) was 16.5 ± 1.3 ml · kg−1· min−1, and the apparent volume of distribution (Vd) was 124.3 ± 9.6 ml/kg. The half-lives of sulfated and nonsulfated gastrin-6 were 2.1 ± 0.3 and 1.9 ± 0.3 min, the MCRs were 42.8 ± 3.7 and 139.4 ± 9.6 ml kg−1min−1( P < 0.01), and the Vdwere 139.0 ± 30.5 and 392.0 ± 81.6 ( P < 0.01) ml kg−1. All pharmacokinetic parameters differed significantly from gastrin-17 ( P < 0.01). We conclude that gastrin 6 has a higher potency but a lower efficacy than gastrin-17. The efficacy of gastrin-6 is increased by tyrosine O-sulfation, which also enhances the protection against elimination.

Model of the distribution and metabolism of a GnRH superagonist in dogs

1990 ◽  
Vol 258 (3) ◽  
pp. E468-E475
Author(s):  
D. Lacoste ◽  
B. Candas ◽  
M. Normand ◽  
F. Labrie
Keyword(s):  
Apparent Volume ◽  
Volume Of Distribution ◽  
Gonadotropin Releasing Hormone ◽  
Metabolic Clearance ◽  
Sigmoid Function ◽  
Subcutaneous Route ◽  
Metabolic Clearance Rate ◽  
Fractional Rate ◽  
Kinetics Of ◽  
Apparent Volume Of Distribution

The plasma kinetics of [D-Trp6, des-Gly-NH2(10)]gonadotropin-releasing hormone (GnRH) ethylamide was assessed in eight dogs over a period of 8 h after rapid intravenous or subcutaneous injection. Each animal received doses of 0.2, 2, and 20 micrograms/kg body wt iv and 1 and 10 micrograms/kg body wt sc. A two-compartment structure, to which a source compartment was added to represent the subcutaneous route, adequately fits the five kinetics when the apparent volume of distribution follows a plasma concentration-dependent sigmoid function. Despite the nonlinearity, the apparent volume of distribution can be approximated by a constant value of 280 ml/kg body wt for the dynamics corresponding to the three lowest and more physiological doses. The metabolic clearance rate is 4.63 ml.min-1.kg body wt-1. The two exponential components that characterize the two-compartment structure are equal to 0.0348 +/- 0.0053 and 0.00470 +/- 0.00060 min-1, respectively. The agonist injected subcutaneously diffuses to plasma at a fractional rate of 0.0265 +/- 0.0029 min-1. Disposal occurs at a maximal rate of 0.017 and 0.0055 min-1 of the amount of agonist present in the central and peripheral compartments, respectively. The highest fractional exchange rate between compartments reaches 0.01 min-1. As simulated with the model, a continuous infusion of 4.63 ng.min-1.kg body wt-1 leads to a steady state of 1 ng/ml plasma; 90% of that level is reached 7 h after the onset of the subcutaneous input signal. The kinetics of plasma [D-Trp6, des-Gly-NH2(10)]GnRH ethylamide is many times slower than that of the native hormone and of the other GnRH agonists.

Effect of Pesticide Exposure on Human Microsomal Enzyme Induction

1982 ◽  
Vol 1 (2) ◽  
pp. 155-158 ◽  
Author(s):  
R. Uppal ◽  
P.R. Sharma ◽  
R.R. Chaudhury
Keyword(s):  
Half Life ◽  
Pesticide Exposure ◽  
Apparent Volume ◽  
Volume Of Distribution ◽  
Metabolic Clearance ◽  
Microsomal Enzymes ◽  
Metabolic Clearance Rate ◽  
Apparent Volume Of Distribution ◽  
Microsomal Enzyme Induction ◽  
Hepatic Microsomal Enzymes

1 The antipyrine half-life, metabolic clearance rate and the apparent volume of distribution were measured in six subjects handling malathion. These results were compared with six appropriate controls. 2 Occupational exposure of malathion in subjects reduced the antipyrine half-life from 9.18 ± 2.16 h in controls to 4.73 ± 1.65 h. 3 It is concluded that malathion exposure increases the rate of antipyrine elimination, possibly by inducing the hepatic microsomal enzymes.

Comparative metabolic clearance rate, volume of distribution and plasma half-life of human β-lipotropin and acth

Life Sciences ◽  
1978 ◽  
Vol 23 (23) ◽  
pp. 2323-2330 ◽  
Author(s):  
Anthony S. Liotta ◽  
Choh Hao Li ◽  
George C. Schussler ◽  
Dorothy T. Krieger
Keyword(s):  
Clearance Rate ◽  
Half Life ◽  
Volume Of Distribution ◽  
Metabolic Clearance ◽  
Metabolic Clearance Rate ◽  
Plasma Half Life

Resin Haemoperfusion in Levomepromazine Poisoning: Evaluation of Effect on Plasma Drug and Metabolite Levels

1984 ◽  
Vol 3 (6) ◽  
pp. 497-503 ◽  
Author(s):  
P.-A. Hals ◽  
D. Jacobsen
Keyword(s):  
Blood Flow ◽  
Plasma Levels ◽  
Apparent Volume ◽  
Volume Of Distribution ◽  
The Body ◽  
Metabolic Clearance ◽  
Plasma Drug ◽  
The Mean ◽  
Apparent Volume Of Distribution

1 Plasma levels of levomepromazine and two of its major metabolites N-desmethyl-levomepromazine and levomepromazine sulphoxide were studied in two poisoned patients treated with resin haemoperfusion at a constant blood flow of 200 ml/min. 2 The mean haemoperfusion clearance of levomepromazine, N-desmethyl-levomepromazine and levomepromazine sulphoxide was 114, 123 and 151 ml/min, respectively, in patient no. 1, and 153, 148 and 184 ml/min, respectively, in patient no. 2. Patient no. 2 had also ingested amitriptyline, and the mean haemoperfusion clearance of amitriptyline and its metabolite nortriptyline was 183 and 183 ml/min respectively. 3 Haemoperfusion did not seem to alter the elimination profile of levomepromazine or the two metabolites in either patient. 4 We conclude that haemoperfusion is of little value in removing levomepromazine, N-desmethyl-levomepromazine or levomepromazine sulphoxide from the body. This is probably due to the large apparent volume of distribution and the high intrinsic hepatic metabolic clearance of these compounds.

Metabolic clearance rate in sheep of a met-enkephalin analogue estimated by radioimmunoassay

1982 ◽  
Vol 93 (3) ◽  
pp. 427-433 ◽  
Author(s):  
J. E. Bolton ◽  
J. H. Livesey ◽  
R. A. Donald
Keyword(s):  
Clearance Rate ◽  
Bolus Injection ◽  
Plasma Concentrations ◽  
Volume Of Distribution ◽  
Metabolic Clearance ◽  
Metabolic Clearance Rate ◽  
Time Intervals ◽  
Naturally Occurring ◽  
Specific Radioimmunoassay ◽  
The Mean

A sensitive and specific radioimmunoassay developed for measuring the met-enkephalin analogue d-ala2-met(0)5-ol-enkephalin (DAMME) was used to study the pharmacokinetics of DAMME in the circulation of sheep. Plasma concentrations of DAMME were measured at varying time-intervals after an intravenous bolus injection or following a constant intravenous infusion of the analogue. The mean metabolic clearance rate of DAMME was 2·8 ml/min per kg, the mean circulating half-life was 52 min and the mean volume of distribution was 190 ml/kg. The longer circulating time of the analogue when compared with that of naturally occurring met-enkephalin would appear to explain its prolonged analgesic effect.

scholarly journals Effect of pregnancy on the metabolic clearance rate and the volume of distribution of oxytocin in the baboon

1998 ◽  
Vol 274 (5) ◽  
pp. E791-E795 ◽  
Author(s):  
Wlodzimierz B. Kowalski ◽  
Lubomir Diveky ◽  
Ramkrishna Mehendale ◽  
Michael Parsons ◽  
Laird Wilson
Keyword(s):  
Clearance Rate ◽  
Volume Of Distribution ◽  
Pharmacokinetic Parameters ◽  
Metabolic Clearance ◽  
Metabolic Clearance Rate ◽  
Arterial Access ◽  
Initial Dilution ◽  
Uterine Contractions ◽  
The Mean ◽  
Dilution Volume

Pharmacokinetic parameters of oxytocin (OT) metabolism were determined during the last third of pregnancy and again 4–8 wk after delivery in the baboon. Animals were placed on a tether system with venous and arterial access and a continuous monitoring of uterine contractions during gestation. Two methods of determining OT pharmacokinetics were utilized (bolus injection vs. continuous infusion). The metabolic clearance rate of OT as determined during the bolus trials ( n = 7) was 22.2 ± 1.5 ml ⋅ min−1 ⋅ kg−1in pregnancy and 16.3 ± 1.4 ml ⋅ min−1 ⋅ kg−1postpartum ( P < 0.05), respectively, and 23.7 ± 2.8 vs. 16.9 ± 3.7 ml ⋅ min−1 ⋅ kg−1( P < 0.05), respectively, as determined during the 1-h infusion trials ( n = 4). The initial dilution volume and the volume of distribution at steady state of OT after administration did not differ between pregnant and postpartum animals ( P > 0.05). The mean residence time (MRT) of OT was shorter during pregnancy, 7.7 ± 0.8 vs. 10.8 ± 1.2 min postpartum ( P < 0.05). In summary, OT metabolism during pregnancy in the baboon is characterized by 1) increased clearance rate (1.4-fold), 2) accelerated turnover due to the shorter MRT, and 3) unaltered distribution.

Sign in / Sign up

Export Citation Format

Share Document