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Pharmacokinetics - Effect Relations of Glibenclamide and its Metabolites in Humans.

Rydberg, Tony S LU (1997)
Abstract (Swedish)
Popular Abstract in Swedish

Denna avhandling gäller glibenklamid som är vårt vanligaste läkemedel för oralt bruk i behandlingen av diabetes mellitus, typ 2 (åldersdiabetes). Glibenklamids upptag, fördelning, omsättning och utsöndring har studerats i detalj hos friska människor samt hos patienter med diabetes. Därtill har läkemedlets och dess metaboliters kinetik relaterats till farmako-dynamiska effekter i kroppen. Avhandlingen bygger på sex delarbeten (I - VI), se artikellistan nedan.



Till att börja med har utvecklats en känslig och specifik vätske-kromatografisk analysmetod som har möjliggjort bestämning av mycket låga koncentrationer av glibenklamid och metaboliter i blodserum och urin från människa... (More)
Popular Abstract in Swedish

Denna avhandling gäller glibenklamid som är vårt vanligaste läkemedel för oralt bruk i behandlingen av diabetes mellitus, typ 2 (åldersdiabetes). Glibenklamids upptag, fördelning, omsättning och utsöndring har studerats i detalj hos friska människor samt hos patienter med diabetes. Därtill har läkemedlets och dess metaboliters kinetik relaterats till farmako-dynamiska effekter i kroppen. Avhandlingen bygger på sex delarbeten (I - VI), se artikellistan nedan.



Till att börja med har utvecklats en känslig och specifik vätske-kromatografisk analysmetod som har möjliggjort bestämning av mycket låga koncentrationer av glibenklamid och metaboliter i blodserum och urin från människa (Delarbete I). Därefter har med hjälp av den utvecklade metodiken påvisats att eliminationen av glibenklamid ur människokroppen är betydligt lång-sammare än vad som tidigare antagits (Delarbete II). Detta är av kliniskt värde eftersom resultaten kan hjälpa till att förklara varför läkemedlet i fråga har så lång verkningstid och varför detta läkemedel ibland kan ge upphov till mycket långa och därigenom farliga tillstånd med underskott på socker i blod.



I avhandlingen har visats att de två huvudmetaboliterna av glibenklamid är aktiva hos människa, något som tidigare har förnekats av många diabetes-forskare och kliniskt verksamma läkare (Delarbete III). Metaboliternas kinetik, dvs det sätt på vilket kroppen påverkar dessa substanser, har undersökts hos både friska människor samt patienter med diabetes under olika betingelser. Olika farmakokinetiska parametrar har beräknats och jämförts mellan metaboliterna och modersubstansen (Delarbete IV). Kinetiken har relaterats till den blodsockersänkande effekten av läkemedlet och de två huvudmetaboliterna och därvid har ett komplext samband beskrivits (Delarbete V). Vidare har kinetiken av glibenklamid och dess aktiva metaboliter undersökts i en grupp av diabetiker med normal njurfunktion samt jämförts med kinetiken i en matchande grupp av patienter med diabetes och varierande grad av nedsatt njurfunktion (Delarbete VI).



I avhandlingsarbetet har kommit fram data som bidrar till att förklara flera tidigare kliniska egendomligheter samtidigt som kliniskt relevant information avseende kinetik-effekt-relationen för detta läkemedel samt dess huvud-metaboliter har kunnat presenteras. (Less)
Abstract
Glibenclamide (Gb) is the most commonly employed sulphonylurea worldwide for the treatment of non-insulin-dependent diabetes mellitus (NIDDM). There has been uncertainty concerning its pharmacokinetics (PK) and pharmacodynamics (PD). Numerous long-lasting hypoglycemic reactions, which have sometimes been fatal, have been reported and have been difficult to reconsile with an allegedly short elimination half-life of Gb and presumedly low hypoglycemic activity of the metabolites, 4-trans-hydroxy-glibenclamide (M1) and 3-cis-hydroxy-glibenclamide (M2). Therefore, the objective of this thesis was to investigate the pharmacokinetics and concentration - effect relations of Gb and these two major metabolites. A simple liquid chromatographic method... (More)
Glibenclamide (Gb) is the most commonly employed sulphonylurea worldwide for the treatment of non-insulin-dependent diabetes mellitus (NIDDM). There has been uncertainty concerning its pharmacokinetics (PK) and pharmacodynamics (PD). Numerous long-lasting hypoglycemic reactions, which have sometimes been fatal, have been reported and have been difficult to reconsile with an allegedly short elimination half-life of Gb and presumedly low hypoglycemic activity of the metabolites, 4-trans-hydroxy-glibenclamide (M1) and 3-cis-hydroxy-glibenclamide (M2). Therefore, the objective of this thesis was to investigate the pharmacokinetics and concentration - effect relations of Gb and these two major metabolites. A simple liquid chromatographic method was developed for the analysis of low concentrations of Gb (1 ng/mL) and the two metabolites (5 ng/mL). The method was shown to be suitable for pharmacokinetic studies on Gb and its metabolites.



The terminal elimination half-life of Gb was examined in 10 NIDDM subjects after cessation of long-term treatment, and it was concluded that the elimination of Gb during therapeutic conditions and chronic dosing is slower than previously thought. The long terminal half-life may help to explain why Gb may sometimes provoke long-lasting hypoglycemic reactions, and the result adds support to the clinical experience that Gb has a relatively long effect duration and supports the use of once-daily dosage of Gb. The PK of Gb and of its metabolites per se after intravenous administration was studied and compared in 8 healthy volunteers. It was concluded that the two Gb metabolites have similar PK except for volume of distribution (V) and renal clearance (CL).



The PK of Gb and its metabolites was investigated and compared in 11 diabetic patients with impaired renal function (IRF) and 11 diabetic patients with normal renal function (NRF). It was concluded that very small amounts of M1 and M2 were excreted in the urine in the IRF group, and that the fraction excreted correlated significantly with renal function. CL/F for Gb was higher in the IRF group than in the NRF control group. Biliary excretion of Gb and metabolites seems likely. The hypoglycemic and insulin-releasing effect of M1 and M2 was assessed after intravenous administration of each metabolite in a placebo-controlled, randomized, single-blind crossover study. It was found that both metabolites have a marked hypoglycemic effect.



The relationship between serum concentrations of Gb, M1 and M2 and their respective effects on blood glucose levels was studied. While there was no simple, direct relationship between drug concentrations and the hypoglycemic effect, consideration of PK and PD time dependencies by means of population PK/PD modelling demonstrated a relationship, involving both Gb and its active metabolites. It was concluded that the major metabolites contribute to the hypoglycemic effect subsequent in vivo formation in the body, that at low concentrations they may have higher activity and a longer effect duration than the parent drug per se. This should be clinically relevant. (Less)
Please use this url to cite or link to this publication:
author
opponent
  • Professor Paalzow, Lennart, Department of Pharmacy, Division of Biopharmaceutics and Pharmacokinetics, Biomedical Centre, Uppsala University, Uppsala, Sweden.
organization
publishing date
type
Thesis
publication status
published
subject
keywords
renal insufficiency., insulin, glucose, non-insulin dependent, diabetes mellitus, pharmacodynamic modelling, pharmacodynamics, pharmaco-kinetics, HPLC method, Glibenclamide, sulphonylurea, metabolites, Pharmacological sciences, pharmacognosy, pharmacy, toxicology, Farmakologi, farmakognosi, farmaci, toxikologi
pages
150 pages
publisher
Apoteken i Skåne, Stortorget 8, Lejonetpassagen, S-211 34 Malmö, Sweden. Fax: + 46 40 102230
defense location
Lilla Aulan, Medicinskt Forskningscentrum, Malmö University Hospital, Malmö, Sweden.
defense date
1997-06-09 13:15
external identifiers
  • Other:ISRN: LUMEDW / (MECF - 1037) 1-150 (1997) - SE
ISBN
91-628-2574-7
language
English
LU publication?
yes
id
eff798c8-7192-4f2d-8008-e0c1fe9def36 (old id 29333)
date added to LUP
2007-06-13 16:03:13
date last changed
2016-09-19 08:45:10
@misc{eff798c8-7192-4f2d-8008-e0c1fe9def36,
  abstract     = {Glibenclamide (Gb) is the most commonly employed sulphonylurea worldwide for the treatment of non-insulin-dependent diabetes mellitus (NIDDM). There has been uncertainty concerning its pharmacokinetics (PK) and pharmacodynamics (PD). Numerous long-lasting hypoglycemic reactions, which have sometimes been fatal, have been reported and have been difficult to reconsile with an allegedly short elimination half-life of Gb and presumedly low hypoglycemic activity of the metabolites, 4-trans-hydroxy-glibenclamide (M1) and 3-cis-hydroxy-glibenclamide (M2). Therefore, the objective of this thesis was to investigate the pharmacokinetics and concentration - effect relations of Gb and these two major metabolites. A simple liquid chromatographic method was developed for the analysis of low concentrations of Gb (1 ng/mL) and the two metabolites (5 ng/mL). The method was shown to be suitable for pharmacokinetic studies on Gb and its metabolites.<br/><br>
<br/><br>
The terminal elimination half-life of Gb was examined in 10 NIDDM subjects after cessation of long-term treatment, and it was concluded that the elimination of Gb during therapeutic conditions and chronic dosing is slower than previously thought. The long terminal half-life may help to explain why Gb may sometimes provoke long-lasting hypoglycemic reactions, and the result adds support to the clinical experience that Gb has a relatively long effect duration and supports the use of once-daily dosage of Gb. The PK of Gb and of its metabolites per se after intravenous administration was studied and compared in 8 healthy volunteers. It was concluded that the two Gb metabolites have similar PK except for volume of distribution (V) and renal clearance (CL).<br/><br>
<br/><br>
The PK of Gb and its metabolites was investigated and compared in 11 diabetic patients with impaired renal function (IRF) and 11 diabetic patients with normal renal function (NRF). It was concluded that very small amounts of M1 and M2 were excreted in the urine in the IRF group, and that the fraction excreted correlated significantly with renal function. CL/F for Gb was higher in the IRF group than in the NRF control group. Biliary excretion of Gb and metabolites seems likely. The hypoglycemic and insulin-releasing effect of M1 and M2 was assessed after intravenous administration of each metabolite in a placebo-controlled, randomized, single-blind crossover study. It was found that both metabolites have a marked hypoglycemic effect.<br/><br>
<br/><br>
The relationship between serum concentrations of Gb, M1 and M2 and their respective effects on blood glucose levels was studied. While there was no simple, direct relationship between drug concentrations and the hypoglycemic effect, consideration of PK and PD time dependencies by means of population PK/PD modelling demonstrated a relationship, involving both Gb and its active metabolites. It was concluded that the major metabolites contribute to the hypoglycemic effect subsequent in vivo formation in the body, that at low concentrations they may have higher activity and a longer effect duration than the parent drug per se. This should be clinically relevant.},
  author       = {Rydberg, Tony S},
  isbn         = {91-628-2574-7},
  keyword      = {renal insufficiency.,insulin,glucose,non-insulin dependent,diabetes mellitus,pharmacodynamic modelling,pharmacodynamics,pharmaco-kinetics,HPLC method,Glibenclamide,sulphonylurea,metabolites,Pharmacological sciences,pharmacognosy,pharmacy,toxicology,Farmakologi,farmakognosi,farmaci,toxikologi},
  language     = {eng},
  pages        = {150},
  publisher    = {ARRAY(0x8085770)},
  title        = {Pharmacokinetics - Effect Relations of Glibenclamide and its Metabolites in Humans.},
  year         = {1997},
}