Biomedical subjects

A S Gross

Publications and source records attributed to A S Gross.

At least 19 recordsLinked to original sources

PubMed2001

High-performance liquid chromatography-electrospray ionization mass spectrometry method for the measurement of moclobemide and two metabolites in plasma.

A rapid and sensitive liquid chromatography-electrospray ionisation mass spectrometry (HPLC-ESI-MS) assay has been developed for the measurement of moclobemide and metabolites, Ro12-5637 and Ro12-8095, in human plasma. Sample preparation (0.5 ml plasma) involves solid-phase extraction using C18 cartridges. A Nova-Pak phenyl column (Waters, 4 microm, 150x2 mm I.D.) was employed for analyte separation with a mixture of 0.2 M ammonium formate buffer, pH 3.57 and acetonitrile as the mobile phase. The within- and between-day precisions of the assay were <18% and the limit of quantification for all analytes was 0.01 microg/ml. The total run-time was 6 min. The method described was used to measure moclobemide, Ro12-5637 and Ro12-8095 in human plasma following an oral 300 mg dose.

Antidepressive Agents↗

PubMed2001

Simultaneous administration of a cocktail of markers to measure renal drug elimination pathways: absence of a pharmacokinetic interaction between fluconazole and sinistrin, p-aminohippuric acid and pindolol.

AIMS: Previous studies suggest that estimated creatinine clearance, the conventional measure of renal function, does not adequately reflect changes in renal drug handling in some patients, including the immunosuppressed. The aim of this study was to develop and validate a cocktail of markers, to be given in a single administration, capable of detecting alterations in the renal elimination pathways of glomerular filtration, tubular secretion and tubular reabsorption. METHODS: Healthy male subjects (n = 12) received intravenously infused 2500 mg sinistrin (glomerular filtration) and 440 mg p-aminohippuric acid (PAH; anion secretion), and orally administered 100 mg fluconazole (reabsorption) and 15 mg rac-pindolol (cation secretion). The potential interaction between these markers was investigated in a pharmacokinetic study where markers (M) or fluconazole (F) were administered alone or together (M + F). Validated analytical methods were used to measure plasma and urine concentrations in order to quantify the renal handling of each marker. Plasma protein binding of fluconazole was measured by ultrafiltration. All subjects had an estimated creatinine clearance within the normal range. The renal clearance of each marker (mean+/- s.d.) was calculated as the ratio of the amount excreted in urine and the area-under-the-concentration-time curve. Statistical comparisons were made using a paired t-test and 95% confidence intervals were reported. RESULTS: The renal clearances of sinistrin (M: 119 +/- 31 ml min(-1); M + F: 130 +/- 40 ml min(-1); P = 0.32), PAH (M: 469 +/- 145 ml min(-1); M + F: 467 +/- 146 ml min(-1); P = 0.95), R-pindolol (M: 204 +/- 41 ml min(-1); M + F: 190 +/- 41 ml min(-1); P = 0.39; n = 11), S-pindolol (M: 225 +/- 55 ml min(-1); M + F: 209 +/- 60 ml min(-1); P = 0.27; n = 11) and fluconazole (F: 14.9 +/- 3.8 ml min(-1); M + F: 13.6 +/- 3.4 ml min(-1); P = 0.16) were similar when the markers or fluconazole were administered alone (M or F) or as a cocktail (M + F). CONCLUSIONS: This study found no interaction between markers and fluconazole in healthy male subjects, suggesting that a single administration of this cocktail of markers of different renal processes can be used to simultaneously investigate pathways of renal drug elimination.

Administration, Oral↗

PubMed2001

Best practice in therapeutic drug monitoring.

It is the goal of Therapeutic Drug Monitoring (TDM) to use drug concentrations to manage a patient's medication regime and optimise outcome. Limited resources require that drug assays should only be performed when they do contribute to patient management. For this to be the case a therapeutic drug monitoring service has a far greater role than just therapeutic drug measuring. This article describes the roles and functions of a Best Practice TDM service. The features which can and should be strived for in each step of the TDM process-the decision to request a drug level, the biological sample, the request, laboratory measurement, communication of results by the laboratory, clinical interpretation and therapeutic management-are discussed.

Dose-Response Relationship, Drug↗

PubMed2001

Analytical validation for a series of marker compounds used to assess renal drug elimination processes.

Renal drug elimination is determined by glomerular filtration, tubular secretion, and tubular reabsorption. Changes in the integrity of these processes influence renal drug clearance, and these changes may not be detected by conventional measures of renal function such as creatinine clearance. The aim of the current study was to examine the analytic issues needed to develop a cocktail of marker drugs (fluconazole, rac-pindolol, para-aminohippuric acid, sinistrin) to measure simultaneously the mechanisms contributing to renal clearance. High-performance liquid chromatographic methods of analysis for fluconazole, pindolol, para-aminohippuric acid, and creatinine and an enzymatic assay for sinistrin were developed or modified and then validated to allow determination of each of the compounds in both plasma and urine in the presence of all other marker drugs. A pilot clinical study in one volunteer was conducted to ensure that the assays were suitable for quantitating all the marker drugs to the sensitivity and specificity needed to allow accurate determination of individual renal clearances. The performance of all assays (plasma and urine) complied with published validation criteria. All standard curves displayed linearity over the concentration ranges required, with coefficients of correlation greater than 0.99. The precision of the interday and intraday variabilities of quality controls for each marker in plasma and urine were all less than 11.9% for each marker. Recoveries of markers (and internal standards) in plasma and urine were all at least 90%. All markers investigated were shown to be stable when plasma or urine was frozen and thawed. For all the assays developed, there were no interferences from other markers or endogenous substances. In a pilot clinical study, concentrations of all markers could be accurately and reproducibly determined for a sufficient duration of time after administration to calculate accurate renal clearance for each marker. This article presents details of the analytic techniques developed for measuring concentrations of marker drugs for different renal elimination processes administered as a single dose to define the processes contributing to renal drug elimination.

Adrenergic beta-Antagonists↗

PubMed2001

Prolonged thiopentone infusion for neurosurgical emergencies: usefulness of therapeutic drug monitoring.

Serial serum thiopentone concentrations were measured during and following completion of an intravenous infusion of thiopentone in 20 patients with neurosurgical emergencies. The concentration data from a further 55 patients who had had some such measurements were reviewed retrospectively. The patients received an infusion for longer than 24 hours at a rate adjusted to maintain EEG burst suppression. The data were interpreted in terms of thiopentone pharmacokinetics and used to produce statistical models relating to clinical outcomes. In these patients, the one-month mortality rate following commencement of thiopentone treatment was 20%; the mean durations of pupillary and motor unresponsiveness following cessation of an infusion were 22 and 91 hours, respectively. Predictors of a prolonged duration of motor unresponsiveness included a prolonged duration of pupillary unresponsiveness, a low thiopentone clearance and a high maximum serum concentration of thiopentone. From pooled logistic regression, median effective serum thiopentone concentrations (EC50) were found to be 50 mg x l(-1) for recovery of pupillary responsiveness and 12 mg x l(-1) for the recovery of motor responsiveness. Because prolonged high-dose thiopentone leads to prolonged residual serum concentrations, it is difficult to distinguish the residual pharmacological effects of thiopentone from the clinical condition. This study suggests that, based on EC50 values for responses, monitoring of post-infusion serum thiopentone concentrations may help determine whether a patient's clinical state is due to residual thiopentone pharmacological effects.

Adult↗

PubMed2000

Pharmacokinetics and pharmacodynamics of R- and S-gallopamil during multiple dosing.

AIMS: Using a stable isotope technique we investigated the pharmacokinetics and pharmacodynamics of gallopamil after administration of 50 mg pseudoracemic gallopamil every 12 h for 7 doses (72 h). METHODS: Six male healthy volunteers were studied. After the seventh dose the pharmacokinetics and pharmacodynamics were assessed. Serum levels of gallopamil were measured by gas chromatography/mass spectrometry. Effects of gallopamil were measured by ECG recording. RESULTS: The apparent oral clearances (R: 4.8 l min-1 (95% CI: 2.9-6.8); S: 5.5 l min-1 (95% CI: 2.5-8.5)) and half-lives (R: 6.2 h; S: 7.2 h) of R- and S-gallopamil were similar (P >0.05). The serum protein binding (fu R: 0.035 (95% CI: 0.026-0. 045); S: 0.051 (95% CI: 0.033-0.069)) and the renal elimination (% of dose R: 0.49%; S: 0.71%) were enantioselective. Gallopamil had a potent effect on the PR interval (% prolongation 35.7% (95% CI: 14. 0-57.3)). No changes in other electrocardiographic or cardiovascular parameters were observed. CONCLUSIONS: The pharmacokinetics and bioavailability of the racemic drug gallopamil are not stereoselective at steady-state and are therefore not substantially altered compared with the single dose administration of gallopamil.

Area Under Curve↗

PubMed1999

Simultaneous analysis of ketamine and bupivacaine in plasma by high-performance liquid chromatography.

A reversed-phase HPLC technique for the simultaneous measurement of both bupivacaine and ketamine in plasma is described. Plasma samples (0.5 ml) were prepared using a rapid and simple back-extraction technique. Resolution of both analytes and the internal standard, desipramine, from medicines coadministered to surgical paediatric patients was obtained using a 5 microm cyano (CN) (250x4.6 mm) column and a mobile phase comprising methanol-acetonitrile-orthophosphoric acid-0.01 M sodium dihydrogenphosphate (200:80:2:718). Good sensitivity for both analytes was observed using UV detection at a wavelength of 215 nm. The method has been validated according to the criteria established by the Journal of Chromatography B.

Bupivacaine↗

PubMed1999

Influence of grapefruit juice on cisapride pharmacokinetics.

OBJECTIVE: Grapefruit juice increases the oral bioavailability of several drugs metabolized by cytochrome P450 3A4. This study investigated the influence of grapefruit juice on the pharmacokinetics of oral cisapride, a substrate of CYP3A4. METHODS: Fourteen healthy volunteers received in random order 10 mg cisapride (Prepulsid) with 250 mL water or grapefruit juice after an overnight fast. Blood samples were taken for 25 hours and urine was collected for 36 hours after dosing. Plasma concentrations of cisapride and urinary norcisapride were measured by HPLC. The influence of grapefruit juice on pharmacokinetic parameters (mean +/- SD) was assessed with the Wilcoxon matched pairs test for 13 subjects (1 subject did not fast as instructed). RESULTS: Grapefruit juice increased cisapride maximum measured plasma concentration (Cmax; water, 65+/-398 ng/mL; grapefruit juice, 87+/-40 ng/mL; P = .009) and area under the plasma concentration-time curve from 0 to 25 hours [AUC(0-25); water, 418+/-280 h x ng/mL; grapefruit juice, 580+/-289 h x ng/mL; P = .005] and prolonged the time to reach Cmax (water, 1.26+/-0.36 hours; grapefruit juice, 1.72+/-0.55 hours; P = .02). Half-life was not affected. Urinary norcisapride recovery was similar and thus the partial apparent metabolic clearance to norcisapride was lower (P = .046) after grapefruit juice (89.5+/-41.2 mL/min) than after water (121.5+/-54.7 mL/min). There was considerable interindividual variation in the grapefruit juice effect [range of AUC(0-25) grapefruit juice/water ratio, 0.90 to 2.65). CONCLUSIONS: Grapefruit juice increases the oral bioavailability of cisapride, with large interindividual variation in the change in Cmax and AUC. Because cisapride has a wide therapeutic index, the interaction may not be of major clinical significance for efficacy, but further studies are necessary at steady state to rule out the possibility of side effects in susceptible individuals.

Adult↗

PubMed1999

Pharmacokinetics of tolbutamide in ethnic Chinese.

AIMS: Ethnic differences in drug disposition have been described for many drugs. Despite the widespread use of tolbutamide in Asian populations, the pharmacokinetics of tolbutamide, a CYP2C9 substrate, have not been described in ethnic Chinese. METHODS: The pharmacokinetics of tolbutamide (500 mg orally) were studied in 10 young, healthy volunteers (seven male/three female; age 21-29 years), each of whom had four ethnic Chinese grandparents. Plasma concentrations of tolbutamide were measured for 32 h post-dose by high performance liquid chromatography. The concentrations of hydroxytolbutamide and carboxytolbutamide were also measured in urine for 32 h post-dose. Noncompartmental pharmacokinetic parameters were calculated using standard equations and compared with those previously reported in Caucasian subjects using the Mann-Whitney U test. RESULTS: Pharmacokinetic parameters in Chinese (mean+/-s.d.) including Cmax (63+/-11 microg ml(-1)), tmax (median 3.3 h; range 1.6-6.0 h), V/F (9.1+/-1.7 l) and t1/2, (9.1 h; harmonic mean) were similar to the values in Caucasians. CL/F (637+/-88 ml h(-1)) was higher in Chinese than Caucasians. The urinary recoveries of hydroxytolbutamide (13+/-1% of dose) and carboxytolbutamide (68+/-5% of dose) and the partial apparent metabolic clearance (0.15+/-0.02 ml min(-1) kg(-1)) in Chinese were comparable with Caucasians. CONCLUSIONS: The pharmacokinetics of tolbutamide have been described in ethnic Chinese and the disposition is similar to that reported in Caucasians. This study suggests that there is no substantial ethnic difference in the tolbutamide hydroxylase activity of CYP2C9.

Adult↗

PubMed1999

Pharmacokinetics of thiopental enantiomers during and following prolonged high-dose therapy.

BACKGROUND: Thiopental is used as a racemate; however, this is not generally recognized. During conditions of prolonged high-dose therapy, the pharmacokinetics of thiopental may become nonlinear, but whether this derives from one or both enantiomers has not been evaluated. The authors determined the pharmacokinetics of R- and S-thiopental and serum concentrations of R- and S-pentobarbital from prolonged high-dose infusion of thiopental for neuroprotection. METHODS: Twenty patients received a mean thiopental dose of 41.2 g over a mean duration of 95 h. R- and S-thiopental enantiomer serum concentration-time data from 18 patients were fitted with two models: a linear one-compartment model with first-order output, and a nonlinear one-compartment model with Michaelis-Menten output. RESULTS: Nonlinear models were preferred in 16 of 18 patients. Paired analysis indicated that steady state clearance (Clss) and volume of distribution (Vd) were higher for R-thiopental (0.108 vs. 0.096 l/min, P < 0.0001; and 313 vs. 273 l, P < 0.0005, respectively); maximal rate of metabolism (Vm) was higher for S- than for R-thiopental (1.01 vs. 0.86 mg x l(-1) x h(-1), P = 0.02); elimination half-lives did not differ (14.6 vs. 14.7 h, P = 0.8); unbound fractions (f(u)) of R- and S-thiopental were 0.20 and 0.18, respectively, P < 0.0001). The differences in mean Clss, Vd and Vm were not significant when adjusted by f(u). Plasma concentrations of R- and S-pentobarbital were relatively small and unlikely to be of clinical significance. CONCLUSION: The pharmacokinetics of R- and S-thiopental became nonlinear at these doses. The pharmacokinetic differences between R- and S-thiopental, although small, were statistically significant and were influenced by the higher f(u) of R-thiopental.

Adolescent↗

PubMed1998

Best practice in therapeutic drug monitoring.

It is the goal of Therapeutic Drug Monitoring (TDM) to use drug concentrations to manage a patient's medication regimen and optimise outcome. Limited resources require that drug assays should only be performed when they do contribute to patient management. For this to be the case a therapeutic drug monitoring service has a far greater role than just therapeutic drug measuring. This article describes the roles and functions of a Best Practice TDM service. The features which can and should be strived for in each step of the TDM process-the decision to request a drug level, the biological sample, the request, laboratory measurement, communication of results by the laboratory, clinical interpretation and therapeutic management-are discussed.

Drug Monitoring↗

PubMed1998

Relationship between proguanil metabolic ratio and CYP2C19 genotype in a Caucasian population.

AIMS: To investigate the relationship between proguanil metabolic ratio (MR, proguanil/cycloguanil) and CYP2C19 genotype in a Caucasian population. METHODS: Ninety-nine Caucasians (age range: 18-55 years, 54 female, 45 male) were genotyped for CYP2C19 and phenotyped for proguanil oxidation by collecting urine for 8 h after taking 100 mg proguanil hydrochloride. Proguanil and cycloguanil concentrations were measured by h.p.l.c. PCR was employed for CYP2C19 genotyping. RESULTS: The three (3%) individuals who were homozygous for CYP2C19*2 (*2/*2) had the highest proguanil MRs (range: 8.0-134.6). Seventy-three (74%) individuals were homozygous for the wild-type allele (*1/*1) and 23 (23%) were heterozygous (*1/*2). The *1/*1 individuals had lower MRs (median=1.4, range: 0.23-5.9, P=0.003, Mann-Whitney U-test) than the *1/*2 subjects (median=2.5, range: 0.88-7.3). CONCLUSIONS: A CYP2C19 gene-dose effect for proguanil oxidation to cycloguanil was observed, confirming a role for CYP2C19 in cycloguanil formation in vivo. However, there was substantial overlap of proguanil MRs in subjects of different CYP2C19 genotypes, due possibly to variability in the activity of other enzymes contributing to the formation of cycloguanil.

Adolescent↗

PubMed1998

Metabolism of dexfenfluramine in human liver microsomes and by recombinant enzymes: role of CYP2D6 and 1A2.

Dexfenfluramine has been widely used as an appetite suppressant in the treatment of obesity. It was recently shown that the apparent non-renal clearance of dexfenfluramine was significantly lower in poor metabolizers than in extensive metabolisers of debrisoquine which suggested the involvement of the polymorphically expressed enzyme, CYP2D6, in dexfenfluramine metabolism. In this study, human liver microsomes and yeast-expressed recombinant enzymes were used to examine dexfenfluramine metabolism in vitro. In human liver microsomes, the major product of dexfenfluramine was nordexfenfluramine with lesser amounts of a novel metabolite, N-hydroxynordexfenfluramine, and ketone and alcohol derivatives being formed. Eadie-Hofstee plots (v against v/[s]) of nordexfenfluramine formation between 1 and 1000 microM substrate concentration were biphasic in three of four liver microsome samples examined, with mean Km values of 3 and 569 microM for the high and low affinity enzymes, respectively. At a substrate concentration (0.5 microM) around the known therapeutic plasma concentration, there was negligible inhibition of microsomal dexfenfluramine N-dealkylation by sulphaphenazole and ketoconazole, but between 33 and 100% inhibition by quinidine, and 0-58% inhibition by 7,8-naphthoflavone in seven liver samples. In human liver microsomes, there was also a significant correlation (rs= 0.79, n = 10, P < 0.01) between dextromethorphan O-demethylation and dexfenfluramine (at 1 microM) N-dealkylation activities. Dexfenfluramine was a specific inhibitor (IC50 46 microM) of CYP2D6-mediated dextromethorphan O-demethylation in human liver microsomes but did not appreciably inhibit six other cytochrome P450 isoform-selective activities for CYP1A2, 2A6, 2C9, 2C19, 2E1 and 3A activities in human liver microsomes. Yeast-expressed recombinant human CYP2D6 metabolized dexfenfluramine with high affinity (Km 1.6 microM, Vmax 0.18 nmol min(-1) nmol P450(-1)) to nordexfenfluramine which was the sole product observed. Recombinant CYP1A2 was a lower affinity enzyme (Km 301 microM, Vmax 1.12 nmol min(-1) nmol P450(-1)) and produced nordexfenfluramine with small amounts of N-hydroxynordexfenfluramine. This is the first detailed study to examine the in-vitro metabolism of dexfenfluramine in human liver microsomes and by recombinant human P450s. We were able to identify CYP2D6 (high affinity) and CYP1A2 (low affinity) as the major enzymes catalysing the N-dealkylation of dexfenfluramine in human liver microsomes.

Cytochrome P-450 CYP1A2↗

PubMed1997

Modified high-performance liquid chromatographic method to measure both dextromethorphan and proguanil for oxidative phenotyping.

The activities of the polymorphic enzymes cytochromes P450 2D6 and 2C19 can be assessed by administering the probe drugs, dextromethorphan and proguanil, respectively. An existing high-performance liquid chromatographic technique, which measures dextromethorphan and its metabolites, has been modified to also measure proguanil and its polymorphic metabolite, cycloguanil in urine. Proguanil and cycloguanil are assayed in separate aliquots of urine to that used for dextromethorphan/dextrorphan as pretreatment with beta-glucuronidase is required for the analysis of dextrorphan. To assay all four compounds a common extraction procedure is used and a single reversed-phase column and isocratic mobile phase with UV and fluorescence detectors connected in series are required. This technique is specific and sensitive for each analyte (limits of detection, dextrorphan/dextromethorphan/proguanil: 0.1 microgram/ml, cycloguanil: 0.2 microgram/ml). All assays are linear over the concentration ranges investigated (dextromethorphan/dextrorphan: 0.5-10 micrograms/ml, proguanil/cycloguanil: 1-20 micrograms/ml). The method described therefore uses laboratory resources very efficiently for all the assays required for hydroxylation phenotyping using proguanil and dextromethorphan.

Antimalarials↗

PubMed1997

Pharmacokinetics of thiopentone enantiomers following intravenous injection or prolonged infusion of rac-thiopentone.

AIMS: Thiopentone is administered as a racemate (rac-thiopentone) for induction of anaesthesia as well as for neurological and neurosurgical emergencies. The pharmacokinetics and pharmacodynamics of rac-thiopentone have been extensively studied but the component R-(+)- and S-(-)- enantiomers, until very recently, have been largely ignored. METHODS: The present study analyses the pharmacokinetics of R-(+)- and S-(-)-thiopentone in 12 patients given rac-thiopentone intravenously for induction of anaesthesia and five patients given a prolonged infusion of rac-thiopentone used for treatment of intracranial hypertension. RESULTS: The mean total body clearance (CLT) and apparent volume of distribution at steady-state (Vss) showed trends towards higher values for R-(+)- than for S-(-)-thiopentone in both patient groups; CLT and Vss of unbound fractions of R-(+)- and S-(-)-thiopentone, however, did not show these trends. The time courses of R-(+)- and S-(-)- thiopentone serum concentrations were so similar that EEG effect could not be attributed to one or other enantiomer. Serum protein binding for S-(-)-thiopentone was greater than for R-(+)-thiopentone (P = 0.02) and 24 h urinary excretion of R-(+)-thiopentone was greater than for S-(-)-thiopentone (P = 0.03). In one patient, concomitant measurement of CSF and serum thiopentone concentrations found that serum: CSF equilibration of unbound fractions of both enantiomers was essentially complete. CONCLUSIONS: The study was unable to determine any pharmacokinetic difference of clinical significance between the R-(+)- and S-(-)-thiopentone enantiomers and concludes that minor differences in CLT and Vss could be explained by enantioselective difference found in serum protein binding.

Adult↗

PubMed1997

Pharmacokinetics and pharmacodynamics of the enantiomers of gallopamil.

The pharmacokinetics and pharmacodynamics of the enantiomers of the calcium antagonist gallopamil have been investigated in six healthy volunteers. Each subject was studied on five occasions after receiving, in randomized order: placebo, 25 mg of (R)-gallopamil, 25 mg of (S)-gallopamil, 50 mg of pseudoracemic [25 mg of deuterated (S)-gallopamil and 25 mg of (R)-gallopamil] and 100 mg of (R)-gallopamil HCl orally. After separate administration, the apparent oral clearances of both enantiomers were similar [(R), 15.1 +/- 9.9 liters/min; (S), 11.0 +/- 6.0 liters/min], indicating that gallopamil first-pass metabolism is not stereoselective. After coadministration, the apparent oral clearance of each enantiomers decreased [(R), 5.9 +/- 2.8 liters/min; (S), 5.8 +/- 2.66 liters/min], suggesting that a partial saturation of first-pass metabolism occurs because the dose was twice as high than for the single enantiomers. Serum protein binding and renal elimination of gallopamil are stereoselective, favoring (S)-gallopamil. Analysis of urine samples revealed a marked degree of stereoselectivity in the formation of O- and N-dealkyl metabolites. Because these showed opposite stereoselectivity, canceling out each other, the net result was no or only marginal stereoselectivity. Twenty-five milligrams of (S)-gallopamil prolonged the PR interval in all subjects; however, a greater effect was elicited by 50 mg of (RS)-gallopamil. (R)-Gallopamil (100 mg) did not significantly alter the PR interval, although higher concentrations were attained than after the pseudoracemate. Based on a consideration of (S)-gallopamil serum concentrations, a comparable relationship between (S)-gallopamil level and effect occurred after (S)- and (RS)-gallopamil, indicating that the pharmacological effect produced by the racemate could be totally accounted for by the higher concentrations of (S)-gallopamil attained.

Adult↗

PubMed1996

The influence of the sparteine/debrisoquine genetic polymorphism on the disposition of dexfenfluramine.

1. To determine whether dexfenfluramine is a substrate of cytochrome P450 2D6 (CYP2D6), its disposition has been studied in nine extensive (EM) and eight poor metabolizers (PM) of debrisoquine. 2. Following a 30 mg dose of dexfenfluramine hydrochloride, urine was collected in all subjects for 96 h post-dose and plasma samples were collected in 11 subjects (six EMs and five PMs). Dexfenfluramine and nordexfenfluramine were measured in urine by h.p.l.c. and in plasma by g.c. 3. Urinary recovery of dexfenfluramine was greater in PMs than EMs (4136 +/- 1509 micrograms vs 1986 +/- 792 micrograms; 95% CI of difference 926-3374; P < 0.05) whereas that of nordexfenfluramine was similar in both phenotypes (PM: 1753 +/- 411 micrograms vs 1626 +/- 444 micrograms). 4. Dexfenfluramine AUC was higher in PMs (677 +/- 348 micrograms l-1 h) than EMs 359 +/- 250 micrograms l-1 h). The apparent oral clearance of dexfenfluramine was greater in EMs than PMs (93.6 +/- 42.4 l h-1 vs 45.6 +/- 19.5 l h-1; 95% CI of difference 1.2-94.7; P < 0.05). The renal clearance was similar in both phenotypes (EMs: 5.88 +/- 2.83 l h-1; PMs 6.60 +/- 2.01 l h-1), indicating that the higher urinary recovery of dexfenfluramine in PMs reflects higher plasma concentrations, rather than phenotype differences in the renal handling, of dexfenfluramine. 5. The apparent nonrenal clearance of dexfenfluramine was substantially lower (P < 0.05; 95% CI of difference 3.0-94.1) in PMs (39.0 +/- 19.5 l h-1) than EMs (87.6 +/- 41.2 l h-1). 6. There was a significant inverse correlation (rs = 0.776 95% CI-0.31-0.94; n = 11; p = 0.005) between the debrisoquine metabolic ratio and the apparent nonrenal clearance of dexfenfluramine. 7. PMs had a higher incidence of adverse effects (nausea and vomiting) than EMs. 8. In conclusion, the metabolism of dexfenfluramine is impaired in PMs. Thus CYP2D6, the isoenzyme deficient in poor metabolizers of debrisoquine, must catalyse at least one pathway of dexfenfluramine biotransformation.

Adult↗

PubMed1995

Carpal tunnel syndrome: a clinicopathologic study.

We evaluated 44 patients with carpal tunnel syndrome and performed histological evaluations of tenosynovium taken at the time of carpal tunnel release. Age, disease and work history, radiographs, and outcome were assessed. The clinical parameters were then compared with the histologic features to determine if the histology was predictive of the clinical course of carpal tunnel syndrome. We found no significance in the histologic changes in patients with carpal tunnel syndrome when age, duration of symptoms, work history, radiographs, and outcome were evaluated.

Adult↗