TOKS3001 - Medisinsk toksikologi - Sideversjonshistorikk

Kristsof: Omdirigerer til MOL3018

2015-05-04T18:36:56Z

Omdirigerer til MOL3018

← Eldre sideversjon		Sideversjonen fra 4. mai 2015 kl. 18:36
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	#redirect [[~~Faglige notater:~~ MOL3018]]		#redirect [[MOL3018]]

Kristsof: Omdirigerer til Faglige notater: MOL3018

2015-05-04T18:34:52Z

Omdirigerer til Faglige notater: MOL3018

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Vegarot: /* Toxicokinetic Parameters */ pyntet.

2013-05-20T12:46:17Z

Toxicokinetic Parameters: pyntet.

← Eldre sideversjon		Sideversjonen fra 20. mai 2013 kl. 12:46
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	Clearance (Cl) is a term the that describes the volume of plasma that is cleared of X. per unit time, and can be given as the sum of clearances from each of the eliminating organs (<math>Cl_{total}=Cl_{renal}+Cl_{hepatic}+...</math>). The total body clearance is given by <math>Cl=\frac{D_{i.v.}}{AUC}</math>, which gives units of volume/time. Using the relations from above this can be seen to be equivalent to <math>Cl_t=V \times k_{el}</math> for a one-compartment model.		Clearance (Cl) is a term the that describes the volume of plasma that is cleared of X. per unit time, and can be given as the sum of clearances from each of the eliminating organs (<math>Cl_{total}=Cl_{renal}+Cl_{hepatic}+...</math>). The total body clearance is given by <math>Cl=\frac{D_{i.v.}}{AUC}</math>, which gives units of volume/time. Using the relations from above this can be seen to be equivalent to <math>Cl_t=V \times k_{el}</math> for a one-compartment model.

	If more than one dose is given, the dosage interval is given by <math>\tau</math>. Giving a dose either continuously, or with a certain interval, allows one to reach a steady state concentration, where there is a balance between absorption and elimination. By definition, this is equal to <math>5 \times C(t_{1/2})</math>. Equivalent equations for this is:		If more than one dose is given, the dosage interval is given by <math>\tau</math>. Giving a dose either continuously, or with a certain interval, allows one to reach a steady state concentration, where there is a balance between absorption and elimination. By definition, this is equal to <math>5 \times C\left(t_{1/2}\right)</math>. Equivalent equations for this is:
	*<math>C_{ss}=\frac{F\times D}{Cl_t \times \tau}=\frac{F\times D}{k_e\times V \times \tau}</math>		*<math>C_{ss}=\frac{F\times D}{Cl_t \times \tau}=\frac{F\times D}{k_e\times V \times \tau}</math>

	If the steady state is reached by a dosage D every <math>\tau</math>, there is naturally an oscillation of steady state values, given by <math>\frac{C_{ss}^{max}}{C_{ss}^{min}}=e^{k_e \tau}</math>. By replacing the bioavailable dosage per time (<math>\frac{F \times D}{\tau}</math>) with an constant infusion rate <math>k_0</math> on obtains <math> C_{ss}=\frac{k_0}{Cl_t}</math>. Often it is desirable to reach steady state concentration as quickly as possible. In this case a bolus dose that immediately gives <math>C_{ss}</math> in the plasma. This dose is then given by <math>D_{bolus}=C_{ss}\times V</math>.		If the steady state is reached by a dosage D every <math>\tau</math>, there is naturally an oscillation of steady state values, given by <math>\frac{C_{ss}^{max}}{C_{ss}^{min}}=e^{k_e \tau}</math>. By replacing the bioavailable dosage per time <math>\left(\frac{F \times D}{\tau}\right)</math> with an constant infusion rate <math>k_0</math> on obtains <math> C_{ss}=\frac{k_0}{Cl_t}</math>. Often it is desirable to reach steady state concentration as quickly as possible. In this case a bolus dose that immediately gives <math>C_{ss}</math> in the plasma. This dose is then given by <math>D_{bolus}=C_{ss}\times V</math>.

	==Metabolism of xenobiotics==		==Metabolism of xenobiotics==

Kenroger: /* Definitions */

2009-05-17T11:00:58Z

Definitions

← Eldre sideversjon		Sideversjonen fra 17. mai 2009 kl. 11:00
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	''Enteroheptic circulation'': Absorption from small intestine to blood --> liver --> conjugate --> bile --> small intestine --> hydrolyzed --> parent compound --> reasorbed into blood		''Enteroheptic circulation'': Absorption from small intestine to blood --> liver --> conjugate --> bile --> small intestine --> hydrolyzed --> parent compound --> reasorbed into blood

			''Distribution Equilibrium'': A state where consenstrations of a substanse in different organs are in equilibrium with each other.

	===Introduction===		===Introduction===

Kenroger: /* Rate constants and elimination */

2009-05-09T08:32:10Z

Rate constants and elimination

← Eldre sideversjon		Sideversjonen fra 9. mai 2009 kl. 08:32
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	There are several rate constants involved in toxicokinetics. There are elimination and absorption rate constant, <math>k_e</math> and <math>k_a</math>, which describes elimination from and absorption into the central compartment (see below) if the dose is administered e.g. orally. In multi-compartment models there are also distribution and redistribution constants, e.g. <math>k_{12}</math> and <math>k_{21}</math>, which describes rates between the compartments.		There are several rate constants involved in toxicokinetics. There are elimination and absorption rate constant, <math>k_e</math> and <math>k_a</math>, which describes elimination from and absorption into the central compartment (see below) if the dose is administered e.g. orally. In multi-compartment models there are also distribution and redistribution constants, e.g. <math>k_{12}</math> and <math>k_{21}</math>, which describes rates between the compartments.

	An example of a rate constant is the excretion rate constant through the kidney, <math>k_r</math>. In the kidney, glomerular filtration has a certain rate, tubular excretion another, and and reabsorption into the tubules a third. Thus, the excretion from the kidneys is given by <math>k_r=k_{gf}+k_{te}-k_{tr}</math>. Similar models can be made for other organs, both absorbative and eliminative.		An example of a rate constant is the excretion rate constant through the kidney, <math>k_r</math>. In the kidney, glomerular filtration has a certain rate, tubular excretion another, and and reabsorption into the tubules a third. Thus, the excretion from the kidneys is given by <math>k_r=k_{f}+k_{ts}-k_{tr}</math>, where <math>f</math> - feces, <math>ts </math>- tubular secretion and <math>tr</math>- tubular reabsorption. Similar models can be made for other organs, both absorbative and eliminative.

	The elimination rates can follow different rate laws. Generally, in a one-compartment model, there is a first-order rate law, e.g. <math>-\frac{d C(t)}{dt}=k_e * C(t)</math>. Other rate laws hold if e.g. the elimination system is saturated, then <math>-\frac{d C(t)}{dt}=const.</math>.		The elimination rates can follow different rate laws. Generally, in a one-compartment model, there is a first-order rate law, e.g. <math>-\frac{d C(t)}{dt}=k_e * C(t)</math>. Other rate laws hold if e.g. the elimination system is saturated, then <math>-\frac{d C(t)}{dt}=const.</math>.
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	where <math>\beta</math> corresponds to <math>k_{e}</math> above, and can be treated the same way.		where <math>\beta</math> corresponds to <math>k_{e}</math> above, and can be treated the same way.

	If C is measured for e.g. an orally distributed drug there is also an absorption phase where the concentration increases over a certain time.		If C is measured for e.g. an orally distributed drug there is also an absorption phase where the concentration increases over a certain time.

	=== Toxicokinetic Parameters ===		=== Toxicokinetic Parameters ===

Kenroger: /* Definitions */

2009-05-09T08:06:15Z

Definitions

← Eldre sideversjon		Sideversjonen fra 9. mai 2009 kl. 08:06
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	''Bioavailability (F)'': The fraction of a given dose D (X-parent compound) that reaches circulation in an unchanged form.		''Bioavailability (F)'': The fraction of a given dose D (X-parent compound) that reaches circulation in an unchanged form.

			''Enteroheptic circulation'': Absorption from small intestine to blood --> liver --> conjugate --> bile --> small intestine --> hydrolyzed --> parent compound --> reasorbed into blood

	===Introduction===		===Introduction===

Kenroger: /* Introduction */

2009-05-09T08:01:24Z

Introduction

← Eldre sideversjon		Sideversjonen fra 9. mai 2009 kl. 08:01
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	*Blood flow through organs		*Blood flow through organs
	*Absorption of the small intestine		*Absorption of the small intestine
	**Villi and microvilli in the intestine: These greatly increase the intestinal area, so absorption for selected X. is greatly enhanced here.		**Villi and microvilli in the intestine: These greatly increase the intestinal area, so absorption into the blood for selected X. is greatly enhanced here.
	**Active and passive diffusion: Some substances can diffuse directly across tissues, but most require some form of transport proteins. The mechanisms of these proteins determine how effectively and selectively xenobiotics are absorbed.		**Active and passive diffusion: Some substances can diffuse directly across tissues, but most require some form of transport proteins. The mechanisms of these proteins determine how effectively and selectively xenobiotics are absorbed.
	**There is also metabolism in the intestine, by e.g. the cytochrome P450 3A4 (CYP3A4) enzyme which can activate many prodrugs.		**There is also metabolism in the intestine, by e.g. the cytochrome P450 3A4 (CYP3A4) enzyme which can activate many prodrugs.
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	*After being metabolized in the liver many xenobiotics are conjugated and marked for excretion into the bile. The bile is excreted in the small intestine, where the drugs can be un-conjugated and reabsorbed, passing into the liver again. This is called the entero-hepatic circulation, and keeps plasma concentration of xenobiotics low in general.		*After being metabolized in the liver many xenobiotics are conjugated and marked for excretion into the bile. The bile is excreted in the small intestine, where the drugs can be un-conjugated and reabsorbed, passing into the liver again. This is called the entero-hepatic circulation, and keeps plasma concentration of xenobiotics low in general.
	*Other special barriers, such as the blood-brain barrier and the placenta also greatly effect the distribution of xenobiotics.		*Other special barriers, such as the blood-brain barrier and the placenta also greatly effect the distribution of xenobiotics.


	===Compartmental models===		===Compartmental models===

Kenroger: /* Definitions */

2009-05-09T07:55:21Z

Definitions

← Eldre sideversjon		Sideversjonen fra 9. mai 2009 kl. 07:55
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	''Elimination'': Biotransformation, exhalation or excretion of X. X. does not need to be removed from the body, only made unavailable in its original form.		''Elimination'': Biotransformation, exhalation or excretion of X. X. does not need to be removed from the body, only made unavailable in its original form.

			''First pass metabolism'': The metabolism of a X that occurs in liver during the first passage.

			''Bioavailability (F)'': The fraction of a given dose D (X-parent compound) that reaches circulation in an unchanged form.

	===Introduction===		===Introduction===

Beckwith: /* Phase I reactions */

2009-05-06T09:33:12Z

Phase I reactions

← Eldre sideversjon		Sideversjonen fra 6. mai 2009 kl. 09:33
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	===Phase I reactions===		===Phase I reactions===

	Phase I reactions are the primary biotransformation of xenobiotics. This includes oxidation, hydrolysis or reduction, and generally introduces or reveals a functional group that increases the hydrophilicity of the xenobiotic a small amount. One very important oxidase is the cytochrome P-450 (CYP) family which are found in most lifeforms. CYP is a heme-containing enzyme family involved in electron transport. The most common reaction is oxidation of an organic substrate by using molecular oxygen as an electron acceptor, i.e. <math>RH + O_2 + 2H^+ + 2e^- \rightarrow ROH + H_2 O</math>. During the oxidation of certain compounds such as aliphatic alkenes and aromatic hydrocarbonds by CYP highly reactive species called epoxides can be formed. This is called activation of the xenobiotic, in which the metabolite form of the xenobiotic is more reactive than the original form. Epoxides can bind to DNA and are possibly mutagenic or carcinogenic. Therefore, in virtually all cells there are CYP-dependent oxidations there is enzyme called ''epoxide hydrolase'' which reacts the epoxide group with water to produce diols. CYP enzymes are especially prevalent in the liver, and play a vital role in regulating the toxicity of a number of compounds that pass trough the liver.		Phase I reactions are the primary biotransformation of xenobiotics. This includes oxidation, hydrolysis or reduction, and generally introduces or reveals a functional group that increases the hydrophilicity of the xenobiotic a small amount. One very important oxidase is the cytochrome P-450 (CYP) family which are found in most lifeforms. CYP is a heme-containing enzyme family involved in electron transport. The most common reaction is oxidation of an organic substrate by using molecular oxygen as an electron acceptor, i.e. <math>RH + O_2 + 2H^+ + 2e^- \rightarrow ROH + H_2 O</math>. During the oxidation of certain compounds such as aliphatic alkenes and aromatic hydrocarbonds by CYP highly reactive species called epoxides can be formed. This is called activation of the xenobiotic, in which the metabolite form of the xenobiotic is more reactive than the original form. Epoxides can bind to DNA and are possibly mutagenic or carcinogenic. Therefore, in virtually all cells there are CYP-dependent oxidations there is enzyme called ''epoxide hydrolase'' which reacts the epoxide group with water to produce diols. CYP enzymes are especially prevalent in the liver, and play a vital role in regulating the toxicity of a number of compounds that pass trough the liver. Important members of the CYP family are CYP3A4, which metabolises a great variety of compounds, and is present at high concentrations in the liver, CYP1A2 and CYP2D6, which metabolise a many different drugs, among them caffeine. CYP2E1 is less prevalent enzyme, but important since it metabolises small polar molecules such as ethanol.

	=== Phase II reactions ===		=== Phase II reactions ===

Beckwith: /* Phase II reactions */

2009-03-21T17:15:12Z

Phase II reactions

← Eldre sideversjon		Sideversjonen fra 21. mar. 2009 kl. 17:15
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	Conjugation with various groups, such as acetylation, methylation, sulfonation, conjugation with glutathion and glucuronidation are the phase II reactions. In general (with the exception of acetylation and methylation) these cause a large increase in hydrophilicity of the conjugate, which allows the xenobiotic to be easily eliminated. These reactions generally proceed much quicker than the phase I reactions, and can either follow a phase I reaction or proceed directly.		Conjugation with various groups, such as acetylation, methylation, sulfonation, conjugation with glutathion and glucuronidation are the phase II reactions. In general (with the exception of acetylation and methylation) these cause a large increase in hydrophilicity of the conjugate, which allows the xenobiotic to be easily eliminated. These reactions generally proceed much quicker than the phase I reactions, and can either follow a phase I reaction or proceed directly.

	~~Glucoronidation~~ is a major pathway of biotransformation of xenobiotics in humans. In glucoronidation the xenobiotic is conjugated with the cofactor uride diphosphate-~~glucoronic~~ acid, creating a highly water soluble molecule, which can be excreted in urine or bile, depending on the total size of the molecule. This reaction is catalyzed by UDP ~~glycoronsyl transferase~~, and requires a hydroxyl, carboxyl or thiol group (roughly), so this will often follow a phase I reaction that provides such groups. Other important pathways are glutathione conjugation (catalyzed by glutathione -S-transferase) and GSH (glycine-cysteine-glutamic acid) conjugation.		Glucuronidation is a major pathway of biotransformation of xenobiotics in humans. In glucoronidation the xenobiotic is conjugated with the cofactor uride diphosphate-glucuronic acid, creating a highly water soluble molecule, which can be excreted in urine or bile, depending on the total size of the molecule. This reaction is catalyzed by UDP-glucuronosyltransferase, and requires a hydroxyl, carboxyl or thiol group (roughly), so this will often follow a phase I reaction that provides such groups. Other important pathways are glutathione conjugation (catalyzed by glutathione -S-transferase) and GSH (glycine-cysteine-glutamic acid) conjugation.

	''GAH, kan noen som faktisk var på denne forelesningen skrive noe her, notatene hans er forferdelige!''		''GAH, kan noen som faktisk var på denne forelesningen skrive noe her, notatene hans er forferdelige!''