Frans Belpaire

Selective Serotonin Reuptake Inhibitors and Cytochrome P-450 Mediated Drug-Drug Interactions: An Update

The selective serotonin reuptake inhibitors (SSRIs) have become the most prescribed antidepressants in many countries. Although the SSRIs share a common mechanism of action, they differ substantially in their chemical structure, metabolism, and pharmacokinetics. Perhaps the most important difference between the SSRIs is their potential to cause drug-drug interactions through inhibition of cytochrome-P450 (CYP) isoforms. This paper provides an update on both the in vitro and in vivo evidence with respect to CYP-mediated drug-drug interactions with this class of antidepressants. The available evidence clearly indicates that the individual SSRIs display a distinct profile of cytochrome P450 inhibition. Fluvoxamine is a potent CYP1A2 and CYP2C19 inhibitor, and a moderate CYP2C9, CYP2D6, and CYP3A4 inhibitor. Fluoxetine and paroxetine are potent CYP2D6 inhibitors, whereas fluoxetines main metabolite, norfluoxetine, has a moderate inhibitory effect on CYP3A4. Sertraline is a moderate CYP2D6 inhibitor; citalopram appears to have little effect on the major CYP isoforms. Fluoxetine deserves special attention as inhibitory effects on CYP-activity can persist for several weeks after fluoxetine discontinuation because of the long half-life of fluoxetine and its metabolite norfluoxetine. Drug combinations with SSRIs should be assessed on an individual basis. Knowledge regarding the CYP-isoforms involved in the metabolism of the co-administered drug may help clinicians to anticipate and avoid potentially dangerous drug-drug interactions. Anticipated interactions can usually be managed by appropriate dose adjustment and titration of the object drug. In some cases, therapeutic drug monitoring can be useful. Equally well, an SSRI with limited interaction potential may be selected to treat depression in patients that receive other medications.

Tissue fractionation and catecholamines—II: Intracellular distribution patterns of tyrosine hydroxylase, dopa decarboxylase, dopamine-β-hydroxylase, phenylethanolamine N-methyltransferase and monoamine oxidase in adrenal medulla

Abstract The intracellular localization of several enzymes involved in the biosynthesis and metabolism of the catecholamines was investigated in bovine adrenal medulla. Various fractions obtained from a total homogenate by differential centrifugation were analyzed for their enzyme content, on a complete balance-sheet basis, using enzymes and the catecholamines as markers. The results provide evidence that tyrosine hydroxylase, dopa decarboxylase and phenylethanolamine N -methyltransferase which were found in the supernatant, are not contained in the catecholamine containing granules. Furthermore, it is probable that fractionation of tyrosine hydroxylase in sucrose solutions causes adsorption in the nuclear fraction, as proved by fractionation in isotonic potassium chloride solutions. Maximal values of relative sp. act. can be obtained in a large mitochondrial fraction for dopamine-s-hydroxylase, catecholamines, monoamine oxidase and some acid hydrolases. Analysis of this fraction by centrifuging in a density gradient was required for its resolution in three different populations of subcellular particles corresponding, from higher to lower density, to the catecholamine and dopamine-s-hydroxylase containing granules, the lysosomes and the mitochondria respectively. In the course of uptake experiments dopamine was shown to be most rapidly taken up into the granules. From these results, a schematic model in the biosynthesis of catecholamines is proposed, suggesting the existence of an important step between decarboxylation and β-hydroxylation.

Pharmacokinetic and Pharmacodynamic Considerations When Treating Patients with Sepsis and Septic Shock

Sepsis and septic shock are accompanied by profound changes in the organism that may alter both the pharmacokinetics and the pharmacodynamics of drugs. This review elaborates on the mechanisms by which sepsis-induced pathophysiological changes may influence pharmacological processes.Drug absorption following intramuscular, subcutaneous, transdermal and oral administration may be reduced due to a decreased perfusion of muscles, skin and splanchnic organs. Compromised tissue perfusion may also affect drug distribution, resulting in a decrease of distribution volume. On the other hand, the increase in capillary permeability and interstitial oedema during sepsis and septic shock may enhance drug distribution. Changes in plasma protein binding, body water, tissue mass and pH may also affect drug distribution. For basic drugs that are bound to the acute phase reactant α1-acid glycoprotein, the increase in plasma concentration of this protein will result in a decreased distribution volume. The opposite may be observed for drugs that are extensively bound to albumin, as the latter protein decreases during septic conditions.For many drugs, the liver is the main organ for metabolism. The determinants of hepatic clearance of drugs are liver blood flow, drug binding in plasma and the activity of the metabolic enzymes; each of these may be influenced by sepsis and septic shock. For high extraction drugs, clearance is mainly flow-dependent, and sepsis-induced liver hypoperfusion may result in a decreased clearance. For low extraction drugs, clearance is determined by the degree of plasma binding and the activity of the metabolic enzymes. Oxidative metabolism via the cytochrome P450 enzyme system is an important clearance mechanism for many drugs, and has been shown to be markedly affected in septic conditions, resulting in decreased drug clearance.The kidneys are an important excretion pathway for many drugs. Renal failure, which often accompanies sepsis and septic shock, will result in accumulation of both parent drug and its metabolites.Changes in drug effect during septic conditions may theoretically result from changes in pharmacodynamics due to changes in the affinity of the receptor for the drug or alterations in the intrinsic activity at the receptor.The lack of valid pharmacological studies in patients with sepsis and septic shock makes drug administration in these patients a difficult challenge. The patients underlying pathophysiological condition may guide individual dosage selection, which may be guided by measuring plasma concentration or drug effect.

Binding ofβ-adrenoceptor blocking drugs to human serum albumin, to α1-acid glycoprotein and to human serum

SummaryThe binding of 8 β-adrenergic blocking drugs to human serum albumin, to α1-acid glycoprotein and to serum from normal volunteers and from patients with rheumatoid arthritis was studied. Protein binding was determined in vitro using equilibrium dialysis of labelled drug at 25° C. Oxprenolol and propranolol were highly bound to serum, alprenolol, pindolol and timolol to a lesser degree, and atenolol, metoprolol and sotalol were negligibly bound. For the five compounds which were appreciably bound, the mean binding was significantly higher in serum from patients with rheumatoid arthritis than in serum from normal volunteers. For those drugs, binding to α1-acid glycoprotein was higher than to human serum albumin, and binding to a mixture of both proteins approached that to serum from healthy volunteers. For each of these drugs there was a strong correlation between the serum α1-glycoprotein concentration and the percentage binding.

Inhibition of CYP2C9 by selective serotonin reuptake inhibitors: in vitro studies with tolbutamide and (S)-warfarin using human liver microsomes

AbstractObjective: To investigate the in vitro potential of selective serotonin reuptake inhibitors (SSRIs) to inhibit two CYP2C9-catalysed reactions, tolbutamide 4-methylhydroxylation and (S)-warfarin 7-hydroxylation. Methods: The formation of 4-hydroxytolbutamide from tolbutamide and that of 7-hydroxywarfarin from (S)-warfarin as a function of different concentrations of SSRIs and some of their metabolites was studied in microsomes from three human livers. Results: Both tolbutamide 4-methylhydroxylation and (S)-warfarin 7-hydroxylation followed one enzyme Michaelis-Menten kinetics. Kinetic analysis of 4-hydroxytolbutamide formation yielded a mean apparent Michaelis-Menten constant (Km) of 133 μM and a mean apparent maximal velocity (Vmax) of 248 pmol · min−1 · mg−1; formation of 7-hydroxywarfarin yielded a mean Km of 3.7 μM and a mean Vmax of 10.5 pmol · min−1 ·  mg−1. Amongst the SSRIs and some of their metabolites tested, only fluvoxamine markedly inhibited both reactions. The average computed inhibition constant (Ki) values and ranges of fluvoxamine when tolbutamide and (S)-warfarin were used as substrate, were 13.3 (6.4–17.3) μM and 13.0 (8.4–18.7) μM, respectively. The average Ki value of fluoxetine for (S)-warfarin 7-hydroxylation was 87.0 (57.0–125) μM. Conclusion: Amongst the SSRIs tested, fluvoxamine was shown to be the most potent inhibitor of both tolbutamide 4-methylhydroxylation and (S)-warfarin 7-hydroxylation. Fluoxetine, norfluoxetine, paroxetine, sertraline, desmethylsertraline, citalopram, desmethylcitalopram had little or no effect on CYP2C9 activity in vitro. This is consistent with in vivo data indicating that amongst the SSRIs, fluvoxamine has the greatest potential for inhibiting CYP2C9-mediated drug metabolism.

Paroxetine affects metoprolol pharmacokinetics and pharmacodynamics in healthy volunteers

To investigate the effect of multiple‐dose paroxetine intake on the stereoselective pharmacokinetics and the pharmacodynamics of metoprolol.

Tissue fractionation and catecholamines: I—Latency and activation properties of dopamine-β-hydroxylase in adrenal medulla

Abstract Dopamine-β-hydroxylase was studied in fresh preparations of a granule fraction obtained from ox adrenal medulla. Preliminary observations showed that dopamine-β-hydroxylase activity could be increased up to fifteen times by means of various activating procedures, thus suggesting the existence of this enzyme in a latent form. The latency of dopamine-β-hydroxylase was investigated by measuring the difference between the free and total activity of the enzyme. Detailed studies were made concerning the influence of the following various activating procedures: exposure to Triton X-100 and to osmotic shock, treatment with the Waring Blendor and freezing and thawing. Each of these procedures, applied in a graded manner, progressively abolished the latency of dopamine-β-hydroxylase and brought about a concomitant increase in its free activity until ultimately the total activity was attained. The soluble activity, measured after high speed centrifugation, parallels the free activity, suggesting a progressive release of the enzyme from the granules into the soluble phase. On the other hand, dopamine-β-hydroxylase was found not to be activated by incubating or preincubating the granule fraction, whereas the catecholamines in the granules were released to a large extent during these procedures. The results suggest that dopamine-β-hydroxylase is contained in a sac-like structure, which behaves as an osmotic system and is surrounded by a semi-permeable membrane. This could play a role as a rate limiting factor in the biosynthesis of catecholamines.

Binding of oxprenolol and propranolol to serum, albumin and α1-acid glycoprotein in man and other species

Species differences in binding of basic drugs have only occasionally been studied and we have therefore measured the binding of the beta-adrenergic blockers oxprenolol and propranolol in (1) serum of healthy humans, dogs, rats and rabbits and of rabbits with experimental arthritis, (2) a solution of albumin of these species and (3) a solution of human alpha 1-AGP. In humans, dogs, rats and arthritic rabbits, binding of oxprenolol and propranolol was much higher in serum than in albumin solution; in healthy rabbits serum binding was very low and not different from albumin binding. For both drugs, concentration-dependency was seen in serum of dogs, humans and rats and of arthritic rabbits; a similar concentration-dependency was found for human alpha 1-AGP solution, but not for human albumin and for serum of healthy rabbits. Tris (2-butoxyethyl)-phosphate (TBEP), a known displacer of drugs from alpha 1-AGP in humans, decreased binding in serum of all species except the rabbit. For both beta-blockers, species differences in capacity constants were found; species differences in affinity constants were present only for propranolol. These results suggest that in humans, dog and rat, but much less in rabbits, oxprenolol and propranolol bind mainly to alpha 1-AGP and that binding to alpha 1-AGP is more important for oxprenolol than for propranolol.

Influence of hypovolemia on the pharmacokinetics and the electroencephalographic effect of propofol in the rat.

BackgroundHypovolemia decreases the dose requirement for anesthetics, but no data are available for propofol. As it is impossible to study this in patients, a rat model was used in which the influence of hypovolemia on the pharmacokinetics and pharmacodynamics of propofol was investigated. MethodsAnimals were randomly allocated to either a control (n = 9) or a hypovolemia (n = 9) group, and propofol was infused (150 mg · kg−1 · h−1) until isoelectric periods of 5 s or longer were observed in the electroencephalogram. The changes observed in the electroencephalogram were quantified using aperiodic analysis and used as a surrogate measure of hypnosis. The righting reflex served as a clinical measure of hypnosis. ResultsThe propofol dose needed to reach the electroencephalographic end point in the hypovolemic rats was reduced by 60% (P < 0.01). This could be attributed to a decrease in propofol clearance and in distribution volume. Protein binding was similar in both groups. To investigate changes in end organ sensitivity during hypovolemia, the electroencephalographic effect versus effect–site concentration relation was studied. The effect–blood concentration relation was biphasic, exhibiting profound hysteresis in both hypovolemic and control animals. Semiparametric minimization of this hysteresis revealed similar equilibration half-lives in both groups. The biphasic effect–concentration relation was characterized by descriptors showing an increased potency of propofol during hemorrhage. The effect–site concentration at the return of righting reflex was 23% (P < 0.01) lower in the hypovolemic animals, also suggesting an increased end organ sensitivity. ConclusionsAn increased hypnotic effect of propofol occurs during hypovolemia in the rat and can be attributed to changes in both pharmacokinetics and end organ sensitivity.

The oxidative metabolism of metoprolol in human liver microsomes: inhibition by the selective serotonin reuptake inhibitors.

AbstractObjective: Biotransformation of metoprolol to α-hydroxymetoprolol (HM) and O-demethylmetoprolol (ODM) is mediated by CYP2D6. The selective serotonin reuptake inhibitors (SSRIs) are known to inhibit CYP2D6. The aim was to study in vitro the potential inhibitory effect of SSRIs on metoprolol biotransformation. Methods: Using microsomes from two human livers, biotransformation of metoprolol to α-hydroxymetoprolol (HM) and O-demethylmetoprolol (ODM) as a function of the concentrations of the SSRIs and of some of their metabolites was studied. Results: The kinetics of the formation of both metabolites are best described by a biphasic enzyme model. The estimated values of Vmax and kM for the high affinity site are for the α-hydroxylation in human liver HL-1 32 pmol mg−1 min−1 and 75 μmol · l−1 respectively, and in human liver HL-9 39 pmol mg−1 · min−1 and 70 μmol · l−1 respectively; for the O-demethylation in HL-1 131 pmol mg−1 min−1 and 95 μmol · l−1 respectively, and in HL-9 145 pmol mg−1 min−1 and 94 μmol · l−1 respectively. Quinidine is for both pathways a potent inhibitor of the high-affinity site, with Ki values ranging from 0.03 to 0.18 μmol · l−1. Fluoxetine, norfluoxetine and paroxetine are likewise potent inhibitors, with Ki values ranging from 0.30 to 2.1 μmol · l−1 fluvoxamine, sertraline, desmethylsertraline, citalopram and desmethylcitalopram are less potent inhibitors, with Ki values above 10 μmol · l−1. Conclusion: The rank order of the SSRIs for inhibition of metoprolol metabolism is comparable to that reported in the literature for other CYP2D6 substrates, with fluoxetine, norfluoxetine and paroxetine being the most potent. These findings need further investigation to determine their clinical relevance.