In VivoMetabolism of Progestins. V. The Effect of Protocol Design on the Estimated Metabolic Clearance Rate and Volume of Distribution of Medroxyprogesterone Acetate in Women*

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

Journal of Endocrinology ◽

10.1677/joe.0.0930427 ◽

1982 ◽

Vol 93 (3) ◽

pp. 427-433 ◽

Cited By ~ 2

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.

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In vitro metabolism of progestins. III. The metabolic clearance rate of medroxyprogesterone acetate in monkeys

Steroids ◽

10.1016/0039-128x(77)90008-3 ◽

1977 ◽

Vol 29 (3) ◽

pp. 399-406 ◽

Cited By ~ 2

Author(s):

Neal A. Musto ◽

David Nahrwold ◽

Momčilo Miljković ◽

C.Wayne Bardin

Keyword(s):

Medroxyprogesterone Acetate ◽

Clearance Rate ◽

In Vitro Metabolism ◽

Metabolic Clearance ◽

Metabolic Clearance Rate

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

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1998.274.5.e791 ◽

1998 ◽

Vol 274 (5) ◽

pp. E791-E795 ◽

Cited By ~ 1

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.

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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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BLOOD AND URINE CLEARANCE OF LUTEINIZING HORMONE RELEASING HORMONE IN MAN MEASURED BY RADIOIMMUNOASSAY

Journal of Endocrinology ◽

10.1677/joe.0.0600305 ◽

1974 ◽

Vol 60 (2) ◽

pp. 305-314 ◽

Cited By ~ 36

Author(s):

S. L. JEFFCOATE ◽

R. H. GREENWOOD ◽

D. T. HOLLAND

Keyword(s):

Luteinizing Hormone ◽

Clearance Rate ◽

Volume Of Distribution ◽

Metabolic Clearance ◽

Production Rates ◽

Metabolic Clearance Rate ◽

Daily Production ◽

Luteinizing Hormone Releasing Hormone ◽

Releasing Hormone ◽

Lh Rh

SUMMARY The clearance of synthetic luteinizing hormone releasing hormone (LH-RH) after intravenous injection has been investigated in man. Thirteen tests were performed in ten subjects, four of whom were normal, the other six had proven disease of the hypothalamo-pituitary region. The rate of disappearance of LH-RH from the circulation could be represented as a double exponential with half-times of the two components of 5·3 and 27·4 min respectively. The initial volume of distribution was 11·1 ± 1·6 (s.d.) 1 and the metabolic clearance rate 1480 ± 170 (s.d.) 1/day. There was no difference in any of these parameters between normal and abnormal subjects. Between 0·75 and 2·8% of the injected dose was excreted in the urine within 8 h, of which 48% was excreted in the first hour. The daily production rates of LH-RH were calculated from the urinary excretion rates; these gave higher results than production rates calculated from the blood metabolic clearance rate. Possible reasons for this are discussed.

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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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Comparison of canine corticosteroid responses to mean and phasic increases in ACTH

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1982.242.2.e102 ◽

1982 ◽

Vol 242 (2) ◽

pp. E102-E108

Author(s):

C. E. Wood ◽

J. Shinsako ◽

M. F. Dallman

Keyword(s):

Clearance Rate ◽

Volume Of Distribution ◽

Conscious Dogs ◽

Metabolic Clearance ◽

Metabolic Clearance Rate ◽

Plasma Acth ◽

Apparent Paradox ◽

Control Value ◽

Disappearance Time ◽

Arterial Plasma

To determine the dynamics and magnitudes of adrenal corticosteroid responses to ACTH, we measured arterial plasma ACTH and corticosteroid concentrations in conscious dogs during infusions of ACTH or saline. Synthetic alpha 1-24-ACTH was infused at rates of 300,900, or 4,500 ng/30 min either as constant infusions or as three equal short infusions at 10-min intervals. In dogs infused with saline, plasma ACTH fluctuated, whereas corticosteroids did not, suggesting that ACTH is secreted episodically in dogs as in man. The magnitudes of the plasma corticosteroid responses to ACTH infusions were linearly related to the logarithm of the total amount of ACTH infused in 30 min and not to the pattern of administration. In all ACTH infusion experiments, the lag between an increase in arterial ACTH and corticosteroids was not less than 3 min. Mean ACTH half-disappearance time, metabolic clearance rate, and volume of distribution estimated from the different experiments ranged between 1.8 and 2.1 min, 24 and 38 ml . kg-1 . min-1, and 95 and 114 ml/kg, respectively. Collectively, these results explain the apparent paradox that corticosteroid responses to ACTH-releasing stimuli can be initiated before a detectable increase in ACTH above the highest control value (Wood et al. Apparent dissociation of ACTH and corticosteroid responses to ml/kg hemorrhage in conscious dogs. Endocrinology In press).

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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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