Biomedical subjects

E Molden

Publications and source records attributed to E Molden.

6 recordsLinked to original sources

PubMed2006

The complexity of active metabolites in therapeutic drug monitoring of psychotropic drugs.

In therapeutic drug monitoring (TDM) practice of psychotropic agents, it is common to summarize plasma concentrations of parent drugs and metabolites when these are considered equipotent. However, there is no clear definition of the term equipotent and one should be aware that metabolites referred to as equipotent in the literature could display several-fold differences in affinities toward target proteins. The fact that the parent drug and metabolite may have different abilities to penetrate the blood-brain-barrier further complicates the picture. Potential differences in brain distribution imply that various metabolite/drug ratios representing the same total concentration in plasma reflect different active concentrations in the brain. Plasma metabolite/drug ratios could differ extensively according to metabolic phenotype and administration route. An example is risperidone where the plasma metabolite/drug ratio is 30-fold lower in cytochrome P450 2D6 poor metabolizers compared to ultrarapid metabolizers, and four-fold lower after intramuscular compared to oral administration. As risperidone is more lipophilic and less effluxed by P-glycoprotein in the blood-brain-barrier than the active metabolite 9-hydroxyrisperidone, one might speculate that patients with high plasma metabolite/drug ratios obtain lower active concentrations in the brain. However, the relative drug-metabolite brain distribution needs to be quantified in humans to clarify to what degree drug and metabolite plasma levels reflect active brain concentrations. The present review illustrates the complexity of active metabolites in TDM with focus on amitriptyline, clomipramine, doxepin, imipramine, fluoxetine, venlafaxine and risperidone, all psychotropic drugs where target plasma concentration ranges are based on the sum of parent drug and metabolite. In addition, perspectives on the possibility of using distribution- and activity-weighted plasma concentrations are provided.

Brain↗

PubMed2003

Identification of epoxybergamottin as a CYP3A4 inhibitor in grapefruit peel.

OBJECTIVE: The oral availability of many drugs metabolised by the enzyme cytochrome P(450) 3A4 (CYP3A4) is increased if co-administered with grapefruit juice. Extracts from grapefruit peel have also demonstrated inhibitory activity and, during commercial manufacturing of grapefruit juice, inhibitory components might be squeezed into the juice from the peel. Thus, the aim of this in vitro study was to identify CYP3A4 inhibitors in grapefruit peel. METHODS: Grapefruit peel was extracted with diethyl ether, and the extract was further fractionated by normal-phase chromatography. Fractions demonstrating significant CYP3A4 inhibitory activity, as measured by the relative reduction in N-demethylation of diltiazem in transfected human liver epithelial cells, were subsequently separated by preparative thin-layer chromatography. Constituents of the fractions and isolated compounds were identified by nuclear magnetic resonance spectroscopy. Analysis of diltiazem and N-demethyl-diltiazem was performed using high-performance liquid chromatography. RESULTS: Of the identified components in grapefruit peel, only epoxybergamottin demonstrated a concentration-dependent inhibition of the CYP3A4-mediated N-demethylation of diltiazem. The IC(50) value was calculated to be 4.2+/-1.1 micro M. Coumarins without the furan ring and flavonoids isolated from grapefruit peel did not interfere with the metabolism of diltiazem. The results indicated the presence of other CYP3A4 inhibitors in grapefruit peel, but these agents were lost during the purification process excluding their identification. CONCLUSION: The furanocoumarin epoxybergamottin, present in grapefruit peel, is an inhibitor of CYP3A4. In commercial manufacturing of grapefruit juice, epoxybergamottin is possibly distributed into the juice. During manufacturing, however, epoxybergamottin may be hydrolysed to 6',7'-dihydroxybergamottin, which has been suggested as an important CYP3A4 inhibitor in grapefruit juice.

Cells, Cultured↗

PubMed2001

[Metabolic interactions with statins].

BACKGROUND: Isoenzymes of the cytochrome P450 (CYP) system play a prominent role in drug metabolism, including the HMG-CoA reductase inhibitors (statins). Alteration in metabolic activity is often the underlying mechanism of clinically relevant interactions, thus it is important to make a rational assessment of the risk for metabolic interactions with statins. MATERIAL AND METHODS: Articles covering the field of statin metabolism and related interactions were mainly searched for via PubMed. RESULT: More than 50% of the overall CYP metabolism is mediated through the isoenzyme CYP3A4, which is the main elimination route of simvastatin, lovastatin and atorvastatin. Interaction studies reveal that simvastatin and lovastatin have the highest potential for clinically relevant interactions related to this isoenzyme, most often leading to increased efficacy/toxicity of the statin. Interactions with agents that alter the activity of CYP3A4 can also be expected for atorvastatin. Other statins are to a lesser extent dependent on CYP3A4 in their elimination. Thus, pravastatin, cerivastatin and fluvastatin have a minor potential for interactions linked to this isoenzyme. Interactions associated with CYP2C9-interference may, however, be present for fluvastatin. INTERPRETATION: Since lipid-lowering therapy most often is life-long, the use of statins will frequently be accompanied by the use of multiple drugs, hence the importance of considering the risk for interactions when selecting statins.

Anti-Bacterial Agents↗

PubMed2000

CYP2D6 is involved in O-demethylation of diltiazem. An in vitro study with transfected human liver cells.

OBJECTIVE: In a previous study of diltiazem (DTZ) pharmacokinetics in renal transplant patients, we speculated that a polymorphic enzyme could be involved in O-demethylation of diltiazem. The aim of this in vitro study was to investigate whether O-demethylation of DTZ is mediated by cytochrome P450-2D6 (CYP2D6). METHODS: DTZ was incubated with transfected human liver epithelial (THLE) cells expressing CYP2D6 (T5-2D6 clone). Metabolism of DTZ was studied over a concentration range of 12.5-400 microM and in the presence of quinidine (a CYP2D6 inhibitor) or erythromycin (a CYP3A4 inhibitor). THLE cells lacking CYP2D6 activity (T5-neo clone) were used as control. The culture medium of the cells, in which DTZ was dissolved, was analysed for DTZ and metabolites prior to and after 8 h of incubation using high-performance liquid chromatography (HPLC, UV detection). Authentic O-demethyl-DTZ (Mx) was not available, and this metabolite was therefore not identifiable. RESULTS: Desacetyl-O-demethyl-DTZ (M4) was exclusively produced during incubations of DTZ with THLE cells expressing CYP2D6. The rate of M4 formation was described using Michaelis Menten kinetics in the concentration range of DTZ used. Production of M4 was inhibited by quinidine, but not erythromycin. An unidentified chromatographic peak, which was interpreted to be Mx, showed the same pattern of formation as M4 both in absence and presence of inhibitors. N-demethylated metabolites, formed by CYP3A4, were not observed in any of the cell lines. CONCLUSION: Evidence was provided in vitro that O-demethylation of DTZ is mediated by the polymorphic isoenzyme CYP2D6. Involvement of CYP2D6 in the metabolism of DTZ may have clinical implications regarding pharmacokinetic variability and interactions.

Acetylation↗

PubMed2000

Extensive metabolism of diltiazem and P-glycoprotein-mediated efflux of desacetyl-diltiazem (M1) by rat jejunum in vitro.

The objective of this in vitro study was to investigate both the intestinal metabolism and transport of diltiazem (DTZ) and its major metabolites in rat jejunum. Metabolism experiments were performed with everted sacs, whereas sheets mounted in a symmetrical twin chamber system were used in transport studies. DTZ was rapidly desacetylated by the rat jejunum to the principle metabolite desacetyl-diltiazem (M1). In addition, minor amounts of N-demethyl-diltiazem and desacetyl-N-demethyl-diltiazem were formed. Due to the rapid desacetylation, it proved difficult to study the transport of DTZ in this model. However, the primary metabolite M1 was shown to be subjected to P-glycoprotein (Pgp)-mediated efflux. The flux rate of M1 was 6- to 7-fold higher from the serosal to the luminal compartment than in the opposite direction. Both coadministration of verapamil and Pgp monoclonal antibody dose dependently increased luminal-to-serosal flux and decreased serosal-to-luminal flux. In conclusion, rat jejunum metabolizes DTZ extensively in vitro, and the major primary metabolite M1 is subjected to Pgp-mediated efflux.

ATP Binding Cassette Transporter, Subfamily B↗

PubMed1999

Pharmacokinetic interactions between microemulsion formulated cyclosporine A and diltiazem in renal transplant recipients.

OBJECTIVE: Bilateral cyclosporin A (CsA) and diltiazem pharmacokinetic interactions have previously been investigated, however, not with the new microemulsion preconcentrate formulation of CsA (Sandimmun Neoral). In addition, the pharmacokinetic effects on the pharmacological active metabolites of diltiazem have not previously been investigated. We performed a pharmacokinetic interaction study in renal transplant recipients, measuring both unmetabolised CsA and diltiazem in addition to three of the main metabolites of diltiazem (MA, M1, M2). METHODS: Nine CsA-treated renal transplant patients were treated with diltiazem, 90-120 mg b.i.d., for 4 weeks. Pharmacokinetic investigations were performed both before and at the end of the diltiazem treatment period. Six non-CsA-treated renal transplant patients served as controls of CsA interactions with diltiazem and its metabolites. RESULTS: Diltiazem treatment resulted in a significant mean increase in the area under the concentration time curve (AUC) for CsA of 51(8)% (P < 0.008) and a peak concentration (Cmax) of 34(8)% (P < 0.05), without altering time to peak concentration (tmax). CsA, however, did not significantly influence diltiazem pharmacokinetics, though two of the metabolites (M1 and M2) tended to be increased. CONCLUSIONS: Diltiazem interacts significantly with the pharmacokinetics of CsA in the new microemulsion formulation. Microemulsion-formulated CsA, however, did not show significant interaction with diltiazem pharmacokinetics.

Adult↗