Biomedical subjects

A Rostami-Hodjegan

Publications and source records attributed to A Rostami-Hodjegan.

At least 19 recordsLinked to original sources

PubMed2006

Determination by liquid chromatography-mass spectrometry of clomiphene isomers in the plasma of patients undergoing treatment for the induction of ovulation.

A rapid, sensitive and selective LC-MS method is described for the simultaneous determination of zuclomiphene and enclomiphene in plasma from patients undergoing treatment with clomiphene citrate for the induction of ovulation. Samples spiked with N-didesmethyltamoxifen, the internal standard, were extracted into methyl tertiary butyl ether. The compounds were separated on a Luna C(18) analytical column, and a mobile phase of methanol-water (70:30 v/v) containing 0.05% trifluoroacetic acid at a flow rate of 1ml/min. The limits of determination were 35pg/ml and 7pg/ml for zu- and enclomiphene, respectively. Within-day coefficients of variation ranged from 2.1% to 7.2%.

Chromatography, High Pressure Liquid↗

PubMed2006

Prediction of in vivo drug clearance from in vitro data. I: impact of inter-individual variability.

The Simcyp Population-Based ADME Simulator was used to predict median drug clearances and their associated variance from in vitro data. Fifteen drugs satisfied the entry criteria for the study and the relevant information (in vitro metabolism data and in vivo human clearance values) were collated from the literature. Predicted values of median clearances fell within 2-fold of observed values for 73% of the drugs (oral route) and 78% of the drugs (intravenous route) when microsomal binding was disregarded, and for 93% (oral) and 100% (intravenous) when it was considered. Irrespective of whether microsomal binding was considered, the predicted fold variability fell within 2-fold of the observed variability for 80% (oral) and 67% (intravenous) of the drugs.

Administration, Oral↗

PubMed2006

Prediction of in vivo drug clearance from in vitro data. II: potential inter-ethnic differences.

Potential differences in drug clearance between Japanese and Caucasians were investigated by integrating data on demography, liver size, the abundance of the major cytochromes P450 and in vitro metabolic parameters. Eleven drugs (alprazolam, caffeine, chlorzoxazone, cyclosporine, midazolam, omeprazole, sildenafil, tolbutamide, triazolam, S-warfarin and zolpidem) fulfilled the entry criteria of the study (i.e. the necessary in vitro metabolism data were available and clearance values had been reported both in Caucasians and Japanese). Values of relevant biological variables were obtained from the literature, and clearance predictions were made using the Simcyp Population-Based ADME Simulator. The ratios of observed oral clearance (CLp.o.) values in Caucasians compared with Japanese ranged from 0.6 to 2.8 (integrating data from 82 sources). The CLp.o. values for alprazolam, caffeine and zolpidem were not statistically different between Caucasian and Japanese (p>0.05), whereas those for chorzoxazone, cyclosporine, omeprazole, tolbutamide and triazolam were higher in Caucasians (p<0.05), and those for midazolam, sildenafil and S-warfarin were higher in Japanese (p<0.05). CLp.o. values, predicted from in vitro data, were within 3-fold of observed in vivo values for seven of the 11 drugs in Japanese. Values for the predicted ratios ranged from 1.6 to 4.9. The predicted ratios were not significantly different from observed ratios for cyclosporine, omeprazole, tolbutamide and triazolam. Only partial success in predicting ethnic differences in clearance indicates the need for larger and more reliable databases on relevant variables. With such information, in silico predictions might be used with more confidence to decrease the need for repeating pharmacokinetic studies in different ethnic groups.

Asian People↗

PubMed2006

Prediction of metabolic drug clearance in humans: in vitro-in vivo extrapolation vs allometric scaling.

Previously in vitro-in vivo extrapolation (IVIVE) with the Simcyp Clearance and Interaction Simulator has been used to predict the clearance of 15 clinically used drugs in humans. The criteria for the selection of the drugs were that they are used as probes for the activity of specific cytochromes P450 (CYPs) or have a single CYP isoform as the major or sole contributor to their metabolism and that they do not exhibit non-linear kinetics in vivo. Where data were available for the clearance of the drugs in at least three animal species, the predictions from IVIVE have now been compared with those based on allometric scaling (AS). Adequate data were available for estimating oral clearance (CLp.o.) in 9 cases (alprazolam, sildenafil, caffeine, clozapine, cyclosporine, dextromethorphan, midazolam, omeprazole and tolbutamide) and intravenous clearance in 6 cases (CLi.v.) (cyclosporine, diclofenac, midazolam, omeprazole, theophylline and tolterodine). AS predictions were based on five different methods: (1) simple allometry (clearance versus body weight); (2) correction for maximum life-span potential (CL x MLP); (3) correction for brain weight (CL x BrW); (4) the use of body surface area; and (5) the rule of exponents. A prediction accuracy was indicated by mean-fold error and the Pearson product moment correlation coefficient. Predictions were considered successful if the mean-fold error was <or=2. IVIVE predictions were accurate in 14 of 15 cases (mean-fold error range: 1.02-4.00). All five AS methods were accurate in 13, 11, 10, 10 and 14 cases, respectively. However, in some cases the error of AS exceeded fivefold. On the basis of the current results, IVIVE is more reliable than AS in predicting human clearance values for drugs mainly metabolized by CYP450 enzymes. This suggests that the place of AS methods in pre-clinical drug development warrants further scrutiny.

Animals↗

PubMed2006

Circadian hydrocortisone infusions in patients with adrenal insufficiency and congenital adrenal hyperplasia.

OBJECTIVE: Conventional hydrocortisone therapy in adrenal insufficiency cannot provide physiological replacement. We have explored the potential of circadian delivery of hydrocortisone as proof of concept for such therapy delivered in modified-release tablet formulation. METHODS: We investigated whether the circadian intravenous infusion of hydrocortisone could improve control of ACTH and androgen levels. Two healthy subjects, two patients with Addison's disease and two patients with congenital adrenal hyperplasia (CAH) were studied. RESULTS: In patients on thrice daily oral hydrocortisone, peak serum cortisol levels were higher than in normal subjects and overnight levels were very low. Patients had very high plasma ACTH levels before their morning dose of hydrocortisone, both at the beginning and at the end of their conventional oral therapy: mean +/- SEM 311.8 +/- 123.2 and 311.2 +/- 85.4 ng/l, respectively. In the patients with CAH, serum 17-hydroxyprogesterone levels were also elevated: 550 and 642 nmol/l at the beginning and 550 and 777 nmol/l at the end of conventional treatment, respectively. The overall 24-h mean cortisol levels were similar for conventional oral hydrocortisone and the circadian infusion. At 0700 h, ACTH levels were much higher on conventional treatment than after circadian infusion: mean +/- SEM 311.2 +/- 85.4 vs. 70.5 +/- 45.0 ng/l, respectively (P < 0.05). The same pattern was observed in 17-hydroxyprogesterone levels, which were 550 and 777 nmol/l after conventional treatment and 3 and 64 nmol/l after circadian infusion. CONCLUSIONS: In patients with poor biochemical control of Addison's disease and CAH, a 24-h circadian infusion of hydrocortisone can decrease morning ACTH and 17-hydroxyprogesterone levels to near normal.

17-alpha-Hydroxyprogesterone↗

PubMed2006

A six-year evaluation of methadone prescribing practices at a substance misuse treatment centre in the UK.

OBJECTIVES: To document changes in prescribing practice at a specialized substance misuse service in the UK occurring since the introduction of the 1999 UK National Guidelines on the management of drug misuse, and to explore a possible link between the length of time spent in methadone maintenance therapy (MMT) and the dosage prescribed. METHODS: A retrospective analysis of a computerized prescription database between 1996 and 2002 obtained from Sheffield Care Trust Substance Misuse Service was performed. The relationship between various measures of dosage and the length of time spent in MMT was investigated. RESULTS: In accordance with the 1999 UK National Guidelines, the proportion of injectable methadone prescribed decreased from 22% to 16%. This was offset by an increase in the prescribing of methadone elixir from 74% to 79%. The 'maximum dose' of methadone prescribed correlated significantly with patient retention, explaining 14% of the variation in time spent in MMT. CONCLUSIONS: Our findings indicate that publication of the UK National Guidelines had a measurable effect on prescribing practice at the Service. We found that a higher methadone dose is associated with increased patient retention in MMT. However, as only a maximum of 14% of the variation in the length of stay is related to methadone dose, the importance of other aspects of treatment such as counselling and rehabilitation programmes, should be considered for the successful treatment of opioid abusers.

Humans↗

PubMed2006

A critical evaluation of the experimental design of studies of mechanism based enzyme inhibition, with implications for in vitro-in vivo extrapolation.

The published literature on mechanism based inhibition (MBI) of CYPs was evaluated with respect to experimental design, methodology and data analysis. Significant variation was apparent in the dilution factor, ratio of preincubation to incubation times and probe substrate concentrations used, and there were some anomalies in the estimation of associated kinetic parameters (k(inact), K(I), r). The impact of the application of inaccurate values of k(inact) and K(I) when extrapolating to the extent of inhibition in vivo is likely to be greatest for those compounds of intermediate inhibitory potency, but this also depends on the fraction of the net clearance of substrate subject to MBI and the pre-systemic and systemic exposure to the inhibitor. For potent inhibitors, the experimental procedure is unlikely to have a material influence on the maximum inhibition. Nevertheless, the bias in the values of the kinetic parameters may influence the time for recovery of enzyme activity following re-synthesis of the enzyme. Careful attention to the design of in vitro experiments to obtain accurate kinetic parameters is necessary for a reliable prediction of different aspects of the in vivo consequences of MBI. The review calls for experimental studies to quantify the impact of study design in studies of MBI, with a view to better harmonisation of protocols.

Algorithms↗

PubMed2005

Timing and type of glucocorticoid replacement in adult congenital adrenal hyperplasia.

Congenital adrenal hyperplasia (CAH) is one of the commonest inherited diseases. Treatment during childhood is directed towards obtaining normal growth. There is an extensive literature on management of CAH during childhood but little published on how patients should be treated as adults. CAH results in increased adrenocorticotropic hormone levels driving the adrenal to produce cortisol and thereby excessive cortisol precursors which are predominantly androgenic. In normal individuals there is a marked circadian rhythm in cortisol release with the lowest levels occurring shortly after midnight and rising between 02.00 and 03.00 h to peak at around 06.00-08.00 h after waking. The treatment of choice for children with CAH is hydrocortisone three times daily. There is no consensus on treating adults. A recent survey by the UK Society for Endocrinology showed that hydrocortisone was the most popular steroid, followed by dexamethasone and then prednisolone. Sixty percent of respondents used a reverse circadian pattern of glucocorticoid treatment and only 16% used a dose based on weight or surface area. In a recent study we demonstrated that the most important variable determining hydrocortisone bioavailability is weight and we advocated a weight-related dosing regimen monitored using a nomogram for serum cortisol. .

Adrenal Hyperplasia, Congenital↗

PubMed2005

Preliminary evidence of the cardiovascular effects of polysubstance misuse in nightclubs.

Adverse reactions to polysubstance misuse are common in nightclubs, yet little is known of the physiological effects of polysubstance misuse in this environment. This study examined the heart rate, blood pressure and oral temperature of 50 participants recruited in a nightclub on four separate nights. In addition, the increase in environmental temperature was recorded throughout each night. There were no differences in oral temperature between polysubstance misusers (i.e. those who used Ecstasy, amphetamine, cocaine, alcohol and cannabis) and alcohol/cannabis misusers. On the other hand, there were significant differences in both heart rate and blood pressure between the two groups. These data suggest that polysubstance misusers may be at risk from cardio- and cerebrovascular toxicity. Further field/on-site work is clearly needed to investigate the effects of polysubstance misuse.

Adolescent↗

PubMed2004

Mechanism-based inactivation of CYP2D6 by methylenedioxymethamphetamine.

The potency of methylenedioxymethamphetamine (MDMA) as a mechanism-based inhibitor of CYP2D6 has been defined using microsomes prepared from yeast expressing the enzyme and from three human livers. The inhibitory effect was increased by preincubation through formation of a metabolic intermediate complex. Inactivation parameters (kinact and KI), defined with respect to the O-demethylation of dextromethorphan, were 0.29 +/- 0.03 (S.E.) min(-1) and 12.9 +/- 3.6 (S.E.) microM for yeast-expressed CYP2D6, and 0.26 +/- 0.02 min(-1) and 14.4 +/- 2.5 microM, 0.15 +/- 0.01 min(-1) and 8.8 +/- 2.6 microM, and 0.12 +/- 0.05 min(-1) and 45.3 +/- 32.1 microM for the liver microsomal preparations. The rate of inactivation of CYP2D6 by MDMA decreased when quinidine, a competitive inhibitor of CYP2D6, was added to the primary incubation mixture. However, inactivation was unaffected by the addition of glutathione. The results indicate that MDMA is a potent mechanism-based inhibitor of CYP2D6, with implications for understanding its in vivo disposition and drug interaction potential.

Cytochrome P-450 CYP2D6↗

PubMed2004

Predicting drug clearance from recombinantly expressed CYPs: intersystem extrapolation factors.

1. Recombinantly expressed human cytochromes P450 (rhCYPs) have been underused for the prediction of human drug clearance (CL). 2. Differences in intrinsic activity (per unit CYP) between rhCYP and human liver enzymes complicate the issue and these discrepancies have not been investigated systematically. We define intersystem extrapolation factors (ISEFs) that allow the use of rhCYP data for the in vitro-in vivo extrapolation of human drug CL and the variance that is associated with interindividual variation of CYP abundance due to genetic and environmental effects. 3. A large database (n = 451) of metabolic stability data has been compiled and used to derive ISEFs for the most commonly used expression systems and CYP enzymes. 4. Statistical models were constructed for the ISEFs to determine major covariates in order to optimize experimental design to increase prediction accuracy. 5. Suggestions have been made for the conduct of future studies using rhCYP to predict human drug clearance.

Algorithms↗

PubMed2003

Determination of midazolam and 1'-hydroxymidazolam by liquid chromatography-mass spectrometry in plasma of patients undergoing methadone maintenance treatment.

A rapid, sensitive and selective LC-MS method was developed for the simultaneous determination of midazolam (MDZ) and 1'-hydroxymidazolam (1'-OHMDZ) in plasma taken from 54 patients undergoing methadone maintenance therapy, most of whom were multidrug users. Samples spiked with prazepam, the internal standard, and were extracted into diethyl ether. Compounds were separated on a Phenomenex Luna C(18) column and a mobile phase of acetonitrile-ammonium acetate buffer (10 mM, pH 4.7) (52:48, v/v) at a flow-rate of 1 ml/min. The limit of detection was 0.65 and 0.68 (ng/ml) for MDZ and 1'-OHMDZ, respectively. Within-day relative standard deviations were less than 8%.

Adjuvants, Anesthesia↗

PubMed2003

A discordance between cytochrome P450 2D6 genotype and phenotype in patients undergoing methadone maintenance treatment.

AIMS: To assess CYP2D6 activity and genotype in a group of patients undergoing methadone maintenance treatment (MMT). METHODS: Blood samples from 34 MMT patients were genotyped by a polymerase chain reaction-based method, and results were compared with CYP2D6 phenotype (n = 28), as measured by the molar metabolic ratio (MR) of dextromethorphan (DEX)/dextrorphan (DOR) in plasma. RESULTS: Whereas 9% of patients (3/34) were poor metabolizers (PM) by genotype, 57% (16/28) were PM by phenotype (P < 0.005). Eight patients, who were genotypically extensive metabolizers (EM), were assigned as PM by their phenotype. The number of CYP2D6*4 alleles and sex were significant determinants of CYP2D6 activity in MMT patients, whereas other covariates (methadone dose, age, weight) did not contribute to variation in CYP2D6 activity. CONCLUSIONS: There was a discordance between genotype and in vivo CYP2D6 activity in MMT patients. This finding is consistent with inhibition of CYP2D6 activity by methadone and may have implications for the safety and efficacy of other CYP2D6 substrates taken by MMT patients.

Adult↗

PubMed2003

Physiologically based modelling of inhibition of metabolism and assessment of the relative potency of drug and metabolite: dextromethorphan vs. dextrorphan using quinidine inhibition.

AIMS: To define the relative antitussive effect of dextromethorphan (DEX) and its primary metabolite dextrorphan (DOR) after administration of DEX. METHODS: Data were analysed from a double-blind, randomized cross-over study in which 22 subjects received the following oral treatments: (i) placebo; (ii) 30 mg DEX hydro-bromide; (iii) 60 mg DEX hydro-bromide; and (iv) 30 mg DEX hydro-bromide preceded at 1 h by quinidine HCl (50 mg). Cough was elicited using citric acid challenge. Pharmacokinetic data from all non-placebo arms of the study were fitted simultaneously. The parameters were then used as covariates in a link PK-PD model of cough suppression using data from all treatment arms. RESULTS: The best-fit PK model assumed two- and one-compartment PK models for DEX and DOR, respectively, and competitive inhibition of DEX metabolism by quinidine. The intrinsic clearance of DEX estimated from the model ranged from 59 to 1536 l x h(-1), which overlapped with that extrapolated from in vitro data (12-261 l x h(-1)) and showed similar variation (26- vs. 21-fold, respectively). The inhibitory effect of quinidine ([I]/Ki) was 19 (95% confidence interval of mean: 18-20) with an estimated average Ki of 0.017 microM. Although DEX and DOR were both active, the potency of the antitussive effect of DOR was 38% that of DEX. A sustained antitussive effect was related to slow removal of DEX/DOR from the effect site (ke0 = 0.07 h(-1)). CONCLUSIONS: Physiologically based PK modelling with perturbation of metabolism using an inhibitor allowed evaluation of the antitussive potency of DOR without the need for separate administration of DOR.

Administration, Oral↗

PubMed2003

Inter-individual variability in levels of human microsomal protein and hepatocellularity per gram of liver.

AIMS: To determine levels of microsomal protein (MPPGL) and hepatocellularity (HPGL) per gram of human liver and their interindividual variability. METHODS: Triplicate liver samples were used to determine values of MPPGL (n = 20) and HPGL (n = 7) after accounting for the fractional loss of microsomal protein or hepatocytes during processing. Repeated measurements from each liver sample allowed the estimation of true interindividual variability in MPPGL and HPGL using ANOVA. RESULTS: The value of MPPGL ranged from 26 to 54 mg g(-1) (mean(geo)= 33 mg g(-1)). The value of HPGL ranged from 65 to 185 x 10(6) cells g(-1) (mean(geo)= 10(7) x 10(6) cells g(-1)). CONCLUSIONS: There is significant interindividual variability in MPPGL, which has implications for the accurate extrapolation of in vitro data on drug metabolism to predict in vivo metabolic clearance.

Adult↗

PubMed2002

Analysis of solvent central nervous system toxicity and ethanol interactions using a human population physiologically based kinetic and dynamic model.

The effect of acute ethanol-mediated inhibition of m-xylene metabolism on central nervous system (CNS) depression in the human worker population was investigated using physiologically based pharmacokinetic (PBPK) models and probabilistic random (Monte Carlo) sampling. PBPK models of inhaled m-xylene and orally ingested ethanol were developed and combined by a competitive enzyme (CYP2E1) inhibition model. Human interindividual variability was modeled by combining estimated statistical distributions of model parameters with the deterministic PBPK models and multiple random or Monte Carlo simulations. A simple threshold pharmacodynamic model was obtained by simulating m-xylene kinetics in human studies where CNS effects were observed and assigning the peak venous blood m-xylene concentration (C(V,max)) as the dose surrogate of toxicity. Probabilistic estimates of an individual experiencing CNS disturbances given exposure to the current UK occupational exposure standard (100 ppm time-weighted average over 8 h), with and without ethanol ingestion, were obtained. The probability of experiencing CNS effects given this scenario increases markedly and nonlinearly with ethanol dose. As CYP2E1-mediated metabolism of other occupationally relevant organic compounds may be inhibited by ethanol, simulation studies of this type should have an increasingly significant role in the chemical toxicity risk assessment.

Administration, Oral↗

PubMed2002

A new rapidly absorbed paracetamol tablet containing sodium bicarbonate. I. A four-way crossover study to compare the concentration-time profile of paracetamol from the new paracetamol/sodium bicarbonate tablet and a conventional paracetamol tablet in fed and fasted volunteers.

The primary objective of this four-way crossover study was to compare the concentration-time profile of paracetamol from a new rapidly absorbed paracetamol tablet containing sodium bicarbonate (PS) with a conventional paracetamol tablet (P), in a panel of 28 fed and fasted healthy volunteers. The results demonstrated that paracetamol was absorbed more rapidly from tablets containing sodium bicarbonate compared to conventional tablets, as indicated by a shorter tmax in both the fed and fasted state and a higher Cmax in the fasted state. The two formulations were bioequivalent with respect to area under curve (AUC). Food did not affect the extent of absorption from either formulation, as indicated by AUC, however, food did reduce the rate of absorption from both formulations, as indicated by a longer tmax and a lower Cmax. Metabolic activation of paracetamol to its oxidation metabolites, as assessed by combined partial clearances to subsequent secondary metabolites cysteine and mercapturic acid conjugates, indicated that the two formulations were bioequivalent in this respect.

Acetaminophen↗

PubMed2002

A new rapidly absorbed paracetamol tablet containing sodium bicarbonate. II. Dissolution studies and in vitro/in vivo correlation.

The objective of this study was to compare the in vitro dissolution profile of a new rapidly absorbed paracetamol tablet containing sodium bicarbonate (PS) with that of a conventional paracetamol tablet (P), and to relate these by deconvolution and mapping to in vivo release. The dissolution methods used include the standard procedure described in the USP monograph for paracetamol tablets, employing buffer at pH 5.8 or 0.05 M HCl at stirrer speeds between 10 and 50 rpm. The mapping process was developed and implemented in Microsoft Excel worksheets that iteratively calculated the optimal values of scale and shape factors which linked in vivo time to in vitro time. The in vitro-in vivo correlation (IVIVC) was carried out simultaneously for both formulations to produce common mapping factors. The USP method, using buffer at pH 5.8, demonstrated no difference between the two products. However, using an acidic medium the rate of dissolution of P but not of PS decreased with decreasing stirrer speed. A significant correlation (r = 0.773; p < .00001) was established between in vivo release and in vitro dissolution using the profiles obtained with 0.05 M HCl and a stirrer speed of 30 rpm. The scale factor for optimal simultaneous IVIVC in the fasting state was 2.54 and the shape factor was 0.16; corresponding values for mapping in the fed state were 3.37 and 0.13 (implying a larger in vitro-in vivo time difference but reduced shape difference in the fed state). The current IVIVC explains, in part, the observed in vivo variability of the two products. The approach to mapping may also be extended to different batches of these products, to predict the impact of any changes of in vitro dissolution on in vivo release and plasma drug concentration-time profiles.

Acetaminophen↗