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

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.

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

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1996.271.1.g156 ◽

1996 ◽

Vol 271 (1) ◽

pp. G156-G163 ◽

Cited By ~ 7

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.

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Effect of Pesticide Exposure on Human Microsomal Enzyme Induction

Human Toxicology ◽

10.1177/096032718200100208 ◽

1982 ◽

Vol 1 (2) ◽

pp. 155-158 ◽

Cited By ~ 4

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.

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

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.2000.279.3.g552 ◽

2000 ◽

Vol 279 (3) ◽

pp. G552-G560 ◽

Cited By ~ 2

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.

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

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.2000.279.5.g903 ◽

2000 ◽

Vol 279 (5) ◽

pp. G903-G909 ◽

Cited By ~ 3

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.

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

Human Toxicology ◽

10.1177/096032718400300604 ◽

1984 ◽

Vol 3 (6) ◽

pp. 497-503 ◽

Cited By ~ 6

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.

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Disposition Kinetics of Amitraz in Lactating Does

Molecules ◽

10.3390/molecules26164769 ◽

2021 ◽

Vol 26 (16) ◽

pp. 4769

Author(s):

Sathish Nanjundappa ◽

Suresh Narayanan Nair ◽

Darsana Udayan ◽

Sreelekha Kanapadinchareveetil ◽

Mathew Jacob ◽

...

Keyword(s):

High Performance ◽

Area Under The Curve ◽

Apparent Volume ◽

Volume Of Distribution ◽

Health Concern ◽

Laboratory Animals ◽

Disposition Kinetics ◽

Kinetics Of ◽

Apparent Volume Of Distribution ◽

Dermal Application

Amitraz, a member of the formamidine pesticide family, commonly used for ectoparasite control, is applied as a dip or low-pressure hand spray to cattle and swine, and the neck collar on dogs. Data on amitraz were generated mainly on laboratory animals, hens, dogs, and baboons. The data on the toxicity and disposition of amitraz in animals and its residues in the milk are inadequate. Therefore, the present study was intended to analyze the disposition kinetics of amitraz and its pattern of elimination in the milk of lactating does after a single dermal application at a concentration of 0.25%. Blood at predetermined time intervals and milk twice daily were collected for eight days post application. The drug concentration was assayed by high-performance liquid chromatography (HPLC). Amitraz was detected in whole blood as early as 0.5 h, which attained a peak concentration at 12 ± 5 h, followed by a steady decline; however, detection persisted until 168 h. Amitraz was present in the blood at its 50% Cmax even after 48 h, and was still detectable after 7 days. The disposition after a single dermal application was best described non-compartmentally. The mean terminal half-life (t1/2), mean residence time (MRT), and area under the curve (AUC0–t) were 111 ± 31 h, 168 ± 39 h, and 539 ± 211 µg/mL/h, respectively. The apparent volume of distribution (Vdarea) was 92 ± 36 mL/g with an observed clearance (Cl) of 0.57 ± 0.33 mL/kg/h. Thus, the drug was well absorbed, widely distributed and slowly eliminated from the animal body. Amitraz achieved milk concentration approximating 0.2 per cent of the total dose after a single exposure and the steady-state elimination of amitraz in milk above the recommended maximum residue limit (MRL) of 0.01 mg/kg can act as a source of public health concern when applied on lactating animals.

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Incremental and decremental kinetics of gastric responses to infused gastrin in dogs

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1982.242.6.g660 ◽

1982 ◽

Vol 242 (6) ◽

pp. G660-G667

Author(s):

B. I. Hirschowitz

Keyword(s):

Volume Of Distribution ◽

Blood Levels ◽

Published Data ◽

Gastric Fistula ◽

Metabolic Clearance ◽

Metabolic Clearance Rate ◽

Molar Basis ◽

Human Gastrin ◽

The Right ◽

Kinetics Of

Acid and pepsin secretion was stimulated by graded doses of synthetic human gastrin I (G-17-I) and pentagastrin (G-5) in six conscious gastric fistula dogs, three with intact vagi and three with fundic vagotomy. Metabolic clearance rate of G-17 was 15.2 ml.kg-1.min-1 and volume of distribution was 15.8%. Gastrin levels decayed in two slopes: t1/2 of 6.8 min and 25-35 min, respectively. These were compared with other published data. Vmax was higher in intact stomachs and at doses or blood levels of gastrin about three to four times smaller. G-17 was almost four times more potent (molar basis) than G-5. Responses were log linearly related to G-17 dose and to serum G-17 during infusion (incremental) and after stopping infusion (decremental). Normalized decremental curves were congruent in all dogs but displaced fivefold (625 vs. 130 pmol/l) to the right at midpoint. Vagotomy changed only association (incremental) kinetics (Km = 352 pmol/l). The previously undescribed difference between blood concentration-effect relationship during drug administration and withdrawal may be important in situations in which blood levels are used as therapeutic guide.

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KINETICS OF 3H-TESTOSTERONE METABOLISM IN PATIENTS WITH CARCINOMA OF THE PROSTATE: EFFECTS OF OESTROGEN ADMINISTRATION

Acta Endocrinologica ◽

10.1530/acta.0.0670733 ◽

1971 ◽

Vol 67 (4) ◽

pp. 733-739 ◽

Cited By ~ 11

Author(s):

C. E. Bird ◽

R. N. Green ◽

R. S. Calandra ◽

J. G. Connolly ◽

A. F. Clark

Keyword(s):

Beneficial Effect ◽

Clearance Rate ◽

Prostatic Carcinoma ◽

Volume Of Distribution ◽

Metabolic Clearance ◽

Oestrogen Therapy ◽

Metabolic Clearance Rate ◽

Testosterone Metabolism ◽

Kinetics Of ◽

Volumes Of Distribution

ABSTRACT We studied the effects of oestrogen administration on the kinetics of testosterone metabolism in patients with prostatic carcinoma. We investigated changes in the metabolic clearance rate, transport and metabolic rate constants and volumes of distribution. In all patients but one, the metabolic clearance rate and volumes of distribution were low during oestrogen administration. The beneficial effect of oestrogen therapy in patients with prostatic carcinoma may be related to the increase in the rate of testosterone metabolism (K2) within a smaller volume of distribution (V1).

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Distribution and kinetics of amylin in humans

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1998.274.5.e903 ◽

1998 ◽

Vol 274 (5) ◽

pp. E903-E908 ◽

Cited By ~ 4

Author(s):

M. Clodi ◽

K. Thomaseth ◽

G. Pacini ◽

K. Hermann ◽

A. Kautzky-Willer ◽

...

Keyword(s):

Apparent Volume ◽

Volume Of Distribution ◽

C Peptide ◽

Fractional Clearance ◽

Cell Hormone ◽

Total Body ◽

Relationship Of ◽

Kinetics Of ◽

Male Subjects ◽

Apparent Volume Of Distribution

The aim of the study was to determine the apparent volume of distribution (VTOT), total body clearance (CL), fractional clearance, and mean residence time (MRT) of the β-cell hormone amylin. We therefore performed an intravenous injection of 50 μg of human synthetic amylin (amlintide) in nine healthy male subjects during suppression of endogenous amylin release by intravenous somatostatin (0.06 μg ⋅ kg−1⋅ min−1). The plasma levels of amylin concentrations over time were analyzed using three-exponential curves. VTOTwas 173 ± 16 ml/kg and was not different from that of insulin reported in the literature (157 ml/kg). MRT was 27.7 ± 2.1 min and thus two times the reported value for insulin (14.1 min) and C-peptide (16.4 min). CL and fractional CL were 6.2 ± 0.2 ml ⋅ kg−1⋅ min−1and 0.038 ± 0.003 min−1, respectively. Fractional CL is therefore definitely lower than that reported for insulin (0.12–0.2 min−1) but is, however, in the range of that of C-peptide (0.05 min−1). In conclusion, clearance of amylin is similar to that reported for C-peptide and much slower than insulin, indicating that the commonly used molar insulin-to-amylin ratio does not reflect the correct relationship of the two peptides.

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