Search PubMed⌕ Search

Biomedical subjects

B B Rasmussen

Publications and source records attributed to B B Rasmussen.

At least 19 recordsLinked to original sources
PubMed2001

Basal muscle amino acid kinetics and protein synthesis in healthy young and older men.

CONTEXT: Sarcopenia is associated with loss of strength and function, eventually leading to loss of independence. Some studies suggest that basal muscle protein turnover is reduced with aging, but other studies do not confirm this finding. OBJECTIVE: To determine if aging per se affects basal muscle protein turnover in men. DESIGN AND SETTING: Cross-sectional study conducted from June 1997 to July 2000 in a general US community. PARTICIPANTS: Twenty-six young (mean [SE] age, 28 [2] years) and 22 older (mean [SE] age, 70 [1] years) men, who were healthy and independent based on activities of daily living, physical examinations, and screening tests. Subjects were excluded if they had cardiac, pulmonary, liver, or kidney disease; any impairment in activities of daily living; or steroid use. MAIN OUTCOME MEASURES: We measured basal muscle protein and amino acid kinetics, based on stable isotope techniques with femoral arteriovenous catheterization and muscle biopsies. Three models (arteriovenous balance, three-pool, and fractional synthesis rate) were used to estimate the metabolic parameters. RESULTS: Mean (SE) total leg volume was 9.60 (0.32) L in older men vs 10.83 (0.43) L in younger men, which suggests muscle loss in the older men. Net muscle protein balance was similar in both groups (older men, - 19 [2] nmol/min per 100 mL of leg volume vs younger men, - 21 [2] nmol/min per 100 mL of leg volume; P =.51). Small differences were found in mean (SE) muscle protein synthesis in comparisons of older vs younger men: arteriovenous balance, 48 (5) nmol/min per 100 mL of leg volume vs 32 (3) nmol/min per 100 mL of leg volume; P =.004; three-pool, 58 (5) nmol/min per 100 mL of leg volume vs 43 (4) nmol/min per 100 mL of leg volume; P =.04; and fractional synthesis rate, 0.0601 (0.0046) %/h vs 0.0578 (0.0047) %/h; P =.73. Small differences were also found in mean (SE) muscle protein breakdown: arteriovenous balance, 66 (5) nmol/min per 100 mL of leg volume in older vs 53 (4) nmol/min per 100 mL of leg volume in younger men, P =.045; and three-pool, 76 (6) nmol/min per 100 mL of leg volume vs 64 (5) nmol/min per 100 mL of leg volume, P =.14. CONCLUSION: Differences in basal muscle protein turnover between older and younger men do not appear to explain muscle loss that occurs with age.

Adult↗
PubMed2001

Value of epidermal growth factor receptor, HER2, p53, and steroid receptors in predicting the efficacy of tamoxifen in high-risk postmenopausal breast cancer patients.

PURPOSE: Few studies have examined the possible importance of biologic prognostic factors in breast cancer connected with differentiation and growth in predicting response to a specific adjuvant treatment. HER2, epidermal growth factor receptor (EGFR), and p53 have all been suggested as possible markers of tamoxifen resistance. The aim of this study was to investigate interactions between adjuvant treatment with tamoxifen and the content of EGFR, HER2, and p53 in steroid receptor-positive patients. PATIENTS AND METHODS: A total of 1,716 high-risk postmenopausal breast cancer patients were randomly assigned to treatment with tamoxifen (868 women) or to observation (848 women) in a prospective trial (Danish Breast Cancer Cooperative Group's 77c protocol). The content of the steroid receptors and expression of p53, EGFR, and HER2 were determined by immunohistochemical analysis of paraffin-embedded tissue. The length of follow-up was 10 years. The end point for this analysis was disease-free survival. RESULTS: Multivariate analysis demonstrated no increased risk of recurrence after treatment with tamoxifen for HER2-, EGFR-, and p53-positive, high-risk, steroid receptor-positive patients. Patients with steroid receptor-positive tumors and positive immunohistochemical staining for HER2, EGFR or p53 benefited from treatment with tamoxifen for 1 year, although the latter variable contained independent prognostic information by itself. CONCLUSION: With the statistical power of the present randomized study, we did not find support for the hypothesis that HER2/EGFR or p53 status predicts benefit from tamoxifen treatment in estrogen receptor-positive patients with early-stage breast cancer. Thus, neither HER2, EGFR, nor p53 overexpression/accumulation should be used as a contraindication for giving tamoxifen.

Aged↗
PubMed2001

Timing of amino acid-carbohydrate ingestion alters anabolic response of muscle to resistance exercise.

The present study was designed to determine whether consumption of an oral essential amino acid-carbohydrate supplement (EAC) before exercise results in a greater anabolic response than supplementation after resistance exercise. Six healthy human subjects participated in two trials in random order, PRE (EAC consumed immediately before exercise), and POST (EAC consumed immediately after exercise). A primed, continuous infusion of L-[ring-(2)H(5)]phenylalanine, femoral arteriovenous catheterization, and muscle biopsies from the vastus lateralis were used to determine phenylalanine concentrations, enrichments, and net uptake across the leg. Blood and muscle phenylalanine concentrations were increased by approximately 130% after drink consumption in both trials. Amino acid delivery to the leg was increased during exercise and remained elevated for the 2 h after exercise in both trials. Delivery of amino acids (amino acid concentration times blood flow) was significantly greater in PRE than in POST during the exercise bout and in the 1st h after exercise (P < 0.05). Total net phenylalanine uptake across the leg was greater (P = 0.0002) during PRE (209 +/- 42 mg) than during POST (81 +/- 19). Phenylalanine disappearance rate, an indicator of muscle protein synthesis from blood amino acids, increased after EAC consumption in both trials. These results indicate that the response of net muscle protein synthesis to consumption of an EAC solution immediately before resistance exercise is greater than that when the solution is consumed after exercise, primarily because of an increase in muscle protein synthesis as a result of increased delivery of amino acids to the leg.

Administration, Oral↗
PubMed2000

Is therapeutic drug monitoring a case for optimizing clinical outcome and avoiding interactions of the selective serotonin reuptake inhibitors?

The selective serotonin reuptake inhibitors (SSRIs) comprise citalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline and they differ from each other in chemical structure, by pharmacokinetic properties and, most importantly, with respect to enzyme-specific metabolism and interactions. Citalopram is administered as a racemic mixture. The drug is oxidated to desmethylcitalopram in the liver, partially by CYP2C19 and partially by CYP3A4. Fluoxetine is administered as a racemate of R- and S-fluoxetine. Both R- and S-fluoxetine are metabolized by CYP2D6 to the active metabolites R- and S-norfluoxetine. Fluvoxamine is metabolized to inactive metabolites by CYP1A2 and CYP2D6. Paroxetine is metabolized to inactive metabolites partially by CYP2D6, and accordingly the metabolism of paroxetine is dependent on the genetic polymorphism of CYP2D6. Sertraline is metabolized to desmethylsertraline, probably by CYP3A4. Several analytical methods have been described for all SSRIs. Most assays are based on separation by high-performance liquid chromatography or gas chromatography. Stereoselective methods for the analysis of racemic citalopram and fluoxetine have been published. The SSRIs are generally well tolerated and their therapeutic indices are large. In several studies there has not been found a clear relationship between clinical efficacy and plasma concentration, nor any threshold that defines toxic concentrations. The available data do not suggest that any benefit be obtained from routine monitoring of SSRI plasma levels. Therefore therapeutic drug monitoring (TDM) of the SSRIs may be useful mainly in situations where poor compliance is suspected and when therapeutic failure or toxic events are experienced at clinically relevant dosages. Further, in special populations, such as in elderly patients, poor metabolizers of sparteine (CYP2D6) or mephenytoin (CYP2C19), and patients with liver impairment, the measurement of plasma concentrations may be useful.

Biotransformation↗
PubMed2000

An oral essential amino acid-carbohydrate supplement enhances muscle protein anabolism after resistance exercise.

This study was designed to determine the response of muscle protein to the bolus ingestion of a drink containing essential amino acids and carbohydrate after resistance exercise. Six subjects (3 men, 3 women) randomly consumed a treatment drink (6 g essential amino acids, 35 g sucrose) or a flavored placebo drink 1 h or 3 h after a bout of resistance exercise on two separate occasions. We used a three-compartment model for determination of leg muscle protein kinetics. The model involves the infusion of ring-(2)H(5)-phenylalanine, femoral arterial and venous blood sampling, and muscle biopsies. Phenylalanine net balance and muscle protein synthesis were significantly increased above the predrink and corresponding placebo value (P < 0.05) when the drink was taken 1 or 3 h after exercise but not when the placebo was ingested at 1 or 3 h. The response to the amino acid-carbohydrate drink produced similar anabolic responses at 1 and 3 h. Muscle protein breakdown did not change in response to the drink. We conclude that essential amino acids with carbohydrates stimulate muscle protein anabolism by increasing muscle protein synthesis when ingested 1 or 3 h after resistance exercise.

Administration, Oral↗
PubMed2000

Androstenedione does not stimulate muscle protein anabolism in young healthy men.

Androstenedione is the immediate precursor of testosterone. Androstenedione intake has been speculated to increase plasma testosterone levels and muscle anabolism. Thus, androstenedione supplements have become widely popular in the sport community to improve performance. This study was designed to determine whether 5 days of oral androstenedione (100 mg/day) supplementation increases skeletal muscle anabolism. Six healthy young men were studied before the treatment period and after 5 days of oral androstenedione supplementation. Muscle protein turnover parameters were compared to those of a control group studied twice as well and receiving no treatment. We measured muscle protein kinetics using a three-compartment model involving infusion of L-[ring-2H5]phenylalanine, blood sampling from femoral artery and vein, and muscle biopsies. Plasma testosterone, androstenedione, LH, and estradiol concentrations were determined by RIA. After ingestion of oral androstenedione, plasma testosterone and LH concentrations did not change from basal, whereas plasma androstenedione and estradiol concentrations were significantly increased (P<0.05). Compared to a control group, androstenedione did not affect muscle protein synthesis and breakdown, or phenylalanine net balance across the leg. We conclude that oral androstenedione does not increase plasma testosterone concentrations and has no anabolic effect on muscle protein metabolism in young eugonadal men.

Adult↗
PubMed2000

The response of muscle protein anabolism to combined hyperaminoacidemia and glucose-induced hyperinsulinemia is impaired in the elderly.

Muscle mass declines with aging. Amino acids alone stimulate muscle protein synthesis in the elderly. However, mixed nutritional supplementation failed to improve muscle mass. We hypothesized that the failure of nutritional supplements is due to altered responsiveness of muscle protein anabolism to increased amino acid availability associated with endogenous hyperinsulinemia. We measured muscle protein synthesis and breakdown, and amino acid transport in healthy young (30 +/- 3 yr) and elderly (72 +/- 1 yr) volunteers in the basal postabsorptive state and during the administration of an amino acid-glucose mixture, using L-[ring-(2)H(5)]phenylalanine infusion, femoral artery and vein catheterization, and muscle biopsies. Basal muscle amino acid turnover was similar in young and elderly subjects. The mixture increased phenylalanine leg delivery and transport into the muscle in both groups. Phenylalanine net balance increased in both groups (young, -27 +/- 8 to 64 +/- 17; elderly, -16 +/- 4 to 29 +/- 7 nmol/(min.100 mL); P: < 0.0001, basal vs. mixture), but the increase was significantly blunted in the elderly (P: = 0.030 vs. young). Muscle protein synthesis increased in the young, but remained unchanged in the elderly [young, 61 +/- 17 to 133 +/- 30 (P: = 0. 005); elderly, 62 +/- 9 to 70 +/- 14 nmol/(min.100 mL) (P: = NS)]. In both groups, protein breakdown decreased (P: = 0.012) and leg glucose uptake increased (P: = 0.0258) with the mixture. We conclude that the response of muscle protein anabolism to hyperaminoacidemia with endogenous hyperinsulinemia is impaired in healthy elderly due to the unresponsiveness of protein synthesis.

Adult↗
PubMed1999

Postoperative radiotherapy in high-risk postmenopausal breast-cancer patients given adjuvant tamoxifen: Danish Breast Cancer Cooperative Group DBCG 82c randomised trial.

BACKGROUND: Postmastectomy radiotherapy is associated with a lower locoregional recurrence rate and improved disease-free and overall survival when combined with chemotherapy in premenopausal high-risk breast-cancer patients. However, whether the same benefits apply also in postmenopausal women treated with adjuvant tamoxifen for similar high-risk cancer is unclear. In a randomised trial among postmenopausal women who had undergone mastectomy, we compared adjuvant tamoxifen alone with tamoxifen plus postoperative radiotherapy. METHODS: Between 1982 and 1990, postmenopausal women with high-risk breast cancer (stage II or III) were randomly assigned adjuvant tamoxifen (30 mg daily for 1 year) alone (689) or with postoperative radiotherapy to the chest wall and regional lymph nodes (686). Median follow-up was 123 months. The endpoints were first site of recurrence (locoregional recurrence, distant metastases, or both), and disease-free and overall survival. FINDINGS: Locoregional recurrence occurred in 52 (8%) of the radiotherapy plus tamoxifen group and 242 (35%) of the tamoxifen only group (p<0.001). In total there were 321 (47%) and 411 (60%) recurrences, respectively. Disease-free survival was 36% in the radiotherapy plus tamoxifen group and 24% in the tamoxifen alone group (p<0.001). Overall survival was also higher in the radiotherapy group (385 vs 434 deaths; survival 45 vs 36% at 10 years, p=0.03). INTERPRETATION: Postoperative radiotherapy decreased the risk of locoregional recurrence and was associated with improved survival in high-risk postmenopausal breast-cancer patients after mastectomy and limited axillary dissection, with 1 year of adjuvant tamoxifen treatment. Improved survival in high-risk breast cancer can best be achieved by a strategy of both locoregional and systemic tumour control.

Antineoplastic Agents, Hormonal↗
PubMed1999

Regulation of fatty acid oxidation in skeletal muscle.

Researchers using animals are beginning to elucidate the control of fatty acid metabolism in muscle at the molecular and enzymatic level. This review examines the physiological data that has been collected from human subjects in the context of the proposed control mechanisms. A number of factors, including the availability of free fatty acids and the abundance of fatty acid transporters, may influence the rate of muscle fatty acid oxidation. However, the predominant point of control appears to be the rate at which fatty acyl-coenzyme A is transported into the mitochondria by the carnitine palmitoyl transferase system. In turn, evidence suggests that the intracellular concentration of malonyl-coenzyme A in muscle is an important regulator of carnitine palmitoyl transferase-I activity. Malonyl-coenzyme A is increased by glucose, which is likely the mechanism whereby glucose intake suppresses the transfer of fatty acids into the mitochondria for subsequent oxidation. In contrast, malonyl-coenzyme A levels decrease during exercise, which enables increased fatty acid oxidation. However, for any given carnitine palmitoyl transferase-I activity, there may be an effect of free fatty acid availability on fatty acid oxidation, particularly at low levels of free fatty acids. Nonetheless, the rate of glucose or glycogen metabolism is probably the primary regulator of the balance between glucose and fatty acid oxidation in muscle.

Animals↗
PubMed1999

In vitro metabolism of quinidine: the (3S)-3-hydroxylation of quinidine is a specific marker reaction for cytochrome P-4503A4 activity in human liver microsomes.

The aim of this study was to evaluate the (3S)-3-hydroxylation and the N-oxidation of quinidine as biomarkers for cytochrome P-450 (CYP)3A4 activity in human liver microsome preparations. An HPLC method was developed to assay the metabolites (3S)-3-hydroxyquinidine (3-OH-Q) and quinidine N-oxide (Q-N-OX) formed during incubation with microsomes from human liver and from Saccharomyces cerevisiae strains expressing 10 human CYPs. 3-OH-Q formation complied with Michaelis-Menten kinetics (mean values of Vmax and Km: 74.4 nmol/mg/h and 74.2 microM, respectively). Q-N-OX formation followed two-site kinetics with mean values of Vmax, Km and Vmax/Km for the low affinity isozyme of 15.9 nmol/mg/h, 76.1 microM and 0.03 ml/mg/h, respectively. 3-OH-Q and Q-N-OX formations were potently inhibited by ketoconazole, itraconazole, and triacetyloleandomycin. Isozyme specific inhibitors of CYP1A2, -2C9, -2C19, -2D6, and -2E1 did not inhibit 3-OH-Q or Q-N-OX formation, with Ki values comparable with previously reported values. Statistically significant correlations were observed between CYP3A4 content and formations of 3-OH-Q and Q-N-OX in 12 human liver microsome preparations. Studies with yeast-expressed isozymes revealed that only CYP3A4 actively catalyzed the (3S)-3-hydroxylation. CYP3A4 was the most active enzyme in Q-N-OX formation, but CYP2C9 and 2E1 also catalyzed minor proportions of the N-oxidation. In conclusion, our studies demonstrate that only CYP3A4 is actively involved in the formation of 3-OH-Q. Hence, the (3S)-3-hydroxylation of quinidine is a specific probe for CYP3A4 activity in human liver microsome preparations, whereas the N-oxidation of quinidine is a somewhat less specific marker reaction for CYP3A4 activity, because the presence of a low affinity enzyme is demonstrated by different approaches.

Algorithms↗
PubMed1998

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

OBJECTIVE: Biotransformation of metoprolol to alpha-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 alpha-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 alpha-hydroxylation in human liver HL-1 32 pmol mg(-1) min(-1) and 75 micromol x l(-1) respectively, and in human liver HL-9 39 pmol mg(-1) x min(-1) and 70 micromol x l(-1) respectively; for the O-demethylation in HL-1 131 pmol mg(-1) min(-1) and 95 micromol x l(-1) respectively, and in HL-9 145 pmol mg(-1) min(-1) and 94 micromol x l(-1) respectively. Quinidine is for both pathways a potent inhibitor of the high-affinity site, with K(i) values ranging from 0.03 to 0.18 micromol x l(-1). Fluoxetine, norfluoxetine and paroxetine are likewise potent inhibitors, with Ki values ranging from 0.30 to 2.1 micromol x l(-1) fluvoxamine, sertraline, desmethylsertraline, citalopram and desmethylcitalopram are less potent inhibitors, with K(i) values above 10 micromol x 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.

1-Naphthylamine↗
PubMed1998

Fluvoxamine is a potent inhibitor of the metabolism of caffeine in vitro.

The selective serotonin re-uptake inhibitor, fluvoxamine, is a very potent inhibitor of CYP1A2, and accordingly causes pharmacokinetic interactions with drugs metabolised by CYP1A2, such as caffeine, theophylline, imipramine, tacrine and clozapine. Interaction between caffeine and fluvoxamine has been described in vivo, leading to lowering of total clearance of caffeine by 80% during fluvoxamine intake. The main purpose of the present study was to evaluate this interaction in vitro in human liver microsomes. A high-performance liquid chromatography method was developed in order to assay 1,3-dimethylxanthine, 1,7-dimethylxanthine, 3,7-dimethylxanthine and 1,3,7-trimethyluric acid formed from caffeine by human liver microsomes. The limit of detection was 0.06 nmol.mg protein-1.hr-1. As expected, fluvoxamine was a very potent inhibitor of the formation of the N-demethylated caffeine metabolites, displaying Ki values of 0.08-0.28 microM. The formation of 1,7-dimethylxanthine was virtually abolished by 10 microM of fluvoxamine, indicating that the N3-demethylation of caffeine is almost exclusively catalysed by CYP1A2. The CYP3A4 inhibitors, ketoconazole and bromocriptine, inhibited 1,3,7-trimethyluric acid formation with Kis of 0.75 microM and 5 microM, respectively, thus further supporting the involvement of CYP3A4 in the 8-hydroxylation of caffeine. The study shows that fluvoxamine, as expected, is a potent inhibitor of the metabolism of caffeine in vitro.

Caffeine↗
PubMed1998

Postexercise recovery of skeletal muscle malonyl-CoA, acetyl-CoA carboxylase, and AMP-activated protein kinase.

Previous studies have demonstrated that oxygen consumption and fat oxidation remain elevated in the postexercise period. The purpose of this study was to determine whether malonyl-CoA, an inhibitor of fatty acid oxidation, remains depressed in muscle after exercise. Rats were sprinted for 5 min (40 m/min, 5% grade) or run for 30 min (21 m/min, 15% grade). Red quadriceps malonyl-CoA returned to resting values by 90 min postexercise in the sprinting rats and remained significantly lower at least 90 min postexercise in the 30-min exercise group. AMP-activated protein kinase activity remained significantly elevated (P < 0.05) for 10 min after exercise in both groups. The most rapid rate of glycogen repletion was in the first 30 min postexercise. The respiratory exchange ratio decreased from a nonexercise value of 0.87 +/- 0.01 to an average 0.82 +/- 0.01 during the 90-min period after 30 min of exercise. Thus muscle malonyl-CoA remains depressed and fat oxidation is elevated for relatively prolonged periods after a single bout of exercise. This may allow fat oxidation to contribute more to muscle energy requirements, thus leaving more glucose for replenishment of muscle glycogen.

AMP-Activated Protein Kinases↗
PubMed1998

Influence of malonyl-CoA and palmitate concentration on rate of palmitate oxidation in rat muscle.

5-Aminoimidazole-4-carboxamide 1-beta-D-ribofuranoside (AICAR) is taken up by perfused skeletal muscle and phosphorylated to form 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuraosyl-5'-monopho sph ate (analog of 5'-AMP) with consequent activation of AMP-activated protein kinase, phosphorylation of acetyl-CoA carboxylase, decrease in malonyl-CoA, and increase in fatty acid oxidation. This study was designed to determine the effect of increasing levels of palmitate on the rate of fatty acid oxidation. Malonyl-CoA concentration was manipulated with AICAR at different palmitate concentrations. Rat hindlimbs were perfused with Krebs-Henseleit bicarbonate containing 4% bovine serum albumin, washed bovine red cells, 200 microU/ml insulin, 10 mM glucose, and different concentrations of palmitate (0. 1-1.0 mM) without or with AICAR (2.0 mM). Perfusion with medium containing AICAR was found to activate AMP-activated protein kinase in skeletal muscle, inactivate acetyl-CoA carboxylase, and decrease malonyl-CoA at all concentrations of palmitate. The rate of palmitate oxidation increased as a function of palmitate concentration in both the presence and absence of AICAR but was always higher in the presence of AICAR. These results provide additional evidence that malonyl-CoA is an important regulator of the rate of fatty acid oxidation at palmitate concentrations in the physiological range.

AMP-Activated Protein Kinases↗
PubMed1997

Fluvoxamine inhibits the CYP2C19-catalyzed bioactivation of chloroguanide.

OBJECTIVE: To investigate the interaction between fluvoxamine and chloroguanide (INN, proguanil) to confirm that fluvoxamine inhibits CYP2C19. METHODS: The study was carried out with a randomized, in vivo, crossover design. Six volunteers were extensive metabolizers of the S-mephenytoin oxidation polymorphism, and six volunteers were poor metabolizers. In period A of the study, each subject took 200 mg chloroguanide orally. In period B, each subject took 100 mg/day fluvoxamine for 8 days and on day 6 ingested 200 mg chloroguanide. In both periods, blood and urine were sampled at regular intervals. Chloroguanide and its two metabolites cycloguanil and 4-chlorphenylbiguanide in plasma and in urine were assayed by means of HPLC. RESULTS: During fluvoxamine use, the median of the total clearance of chloroguanide decreased in a statistically significant way from 1282 ml/min to 782 ml/min among the extensive metabolizers, whereas there was no change among the poor metabolizers. The partial clearance of chloroguanide by means of cydoguanil and 4-chlorphenylbiguanide formation among the extensive metabolizers decreased from 222 ml/min and 97 ml/min before to 33 ml/min and 11 ml/min during fluvoxamine intake, respectively. Among poor metabolizers the corresponding values were 35 ml/min and 7.6 ml/min before and 38 ml/min and 6.9 ml/min during fluvoxamine intake. For each metabolite clearance the change was statistically significant among the extensive metabolizers but not among the poor metabolizers. Both cycloguanil and 4-chlorphenylbiguanide formation clearances were statistically significantly higher among the extensive metabolizers than the poor metabolizers in period A but not in period B (phenocopy). CONCLUSION: Fluvoxamine is an effective inhibitor of CYP2C19.

Administration, Oral↗
PubMed1997

Imipramine demethylation in vivo: impact of CYP1A2, CYP2C19, and CYP3A4.

OBJECTIVE: To further substantiate the role of CYP1A2 and CYP3A4 for the N-demethylation in vivo. At least three different P450s appear to be responsible for the N-demethylation of imipramine to desipramine in vivo: CYP1A2, CYP2C19, and CYP3A4. The role of CYP2C19 in this regard is well documented, but for the two other P450s the evidence is either indirect or based on in vitro studies. METHODS: Phenotypic tests for imipramine N-demethylation, CYP1A2 (caffeine testing), CYP2C19 (mephenytoin and chloroguanide [proguanil] testing), and CYP3A4 (hydrocortisone and quinidine testing) were carried out in 32 healthy young Danes; all were poor (n = 31) or extremely slow extensive metabolizers (n = 1) of sparteine. RESULTS: By exclusion of the insignificant log-transformed variables, multiple regression analysis for In (desipramine/imipramine) showed that only in (mephenytoin S/R) correlated (p = 0.013; r2 = 0.19). For in (2-hydroxydesipramine/2-hydroxyimipramine) we found that in (mephenytoin S/R) and in (4-chlorophenylbiguanide/chloroguanide) correlated (p = 0.001; r2 = 0.41). CONCLUSION: We did not find in vivo evidence of either CYP1A2 or CYP3A4 activity in the N-demethylation of imipramine. This could be due in part to inadequate CYP1A2 and CYP3A4 in vivo function tests.

Adult↗
PubMed1997

Griseofulvin and fluvoxamine interactions with the metabolism of theophylline.

Theophylline is predominantly metabolized by cytochrome P4501A2 (CYP1A2). A possible interaction between griseofulvin and theophylline was reported to our laboratory, which led us to form the hypothesis that griseofulvin induces the metabolism of theophylline. One purpose of this study was to investigate this hypothesis. The study was carried out as a randomized crossover study of 12 healthy volunteers. In period A of the study, each volunteer received a single dose of 300 mg theophylline ethylenediamine orally. In period B, the subjects took fluvoxamine, 50 mg for 1 day and 100 mg for 6 days, and on day 4, the subjects ingested 300 mg theophylline ethylenediamine. Fluvoxamine is a potent inhibitor of CYP1A2, and period B was included as a positive control. In period C, the subjects took 500 mg griseofulvin for 9 days; on day 8 the subjects again ingested 300 mg theophylline ethylenediamine. Theophylline and its metabolites (1-methyluric acid [IMU], 3-methylxanthine [3MX], and 1,3-dimethyluric acid [13DMU]) in plasma and urine were assayed by high-performance liquid chromatography. During fluvoxamine intake, the median of the total clearance of theophylline decreased from 80 ml/min to 24 ml/min, and the half-life increased from 6.6 to 22 h. The partial formation clearances of the metabolites decreased from 17 to 1.7 ml/min, from 8.9 to 0.9 ml/min, and from 21 to 6.8 ml/min for 1MU, 3MX, and 13DMU, respectively. The results confirm that assessment of theophylline metabolism indeed serves as a biomarker for CYP1A2. During griseofulvin ingestion, the median of the total and partial clearances of theophylline were 84 ml/min, 22 ml/min (1MU), 9.4 ml/min (3MX), and 25 ml/min (13DMU). The half-life decreased significantly from 6.6 to 5.7 h. The increase in partial formation clearances of 1MU and 13DMU, but not of 3MX, were statistically significant. The increase in the total clearance reached only borderline significance. In four subjects a marked induction was seen for all pharmacokinetic parameters, suggesting that the susceptibility to induction is more pronounced in some subjects. This susceptibility could theoretically be explained by a polymorphism in the inducibility of the gene coding for the CYP1A2 enzyme.

Adult↗