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Metabolic Clearance (metabolic + clearance)
Selected AbstractsThe relationship between peripheral glucose utilisation and insulin sensitivity in the regulation of hepatic glucose production: studies in normal and alloxan-diabetic dogsDIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue 2 2006M. J. Christopher Abstract Background Hepatic glucose overproduction (HGP) of diabetes could be primary or could occur in response to the metabolic needs of peripheral (skeletal muscle (SkM)) tissues. This question was tested in normal and diabetic dogs. Methods HGP, SkM glucose uptake (Rdtissue), metabolic clearance of glucose (MCRg) and glycolytic flux (GFexog), and SkM biopsies were measured in the same dogs before and after alloxan-induced diabetes. Normal dogs were exposed to (1) an extended 20-h fast, (2) low- and high-dose glucose infusions (GINF) at basal insulinaemia, and chronic diabetic dogs were exposed to (3) hyperglycaemia, (4) phlorizin-induced normoglycaemia, and (5) poor and good diabetic control. Results (1) Prolonged fast: HGP, Rdtissue, and GFexog fell in parallel (p < 0.05). (2) Low-dose GINF: plasma glucose, insulin, Rdtissue, MCRg, and GFexog were unchanged, but HGP fell by ,40%, paralleling the supplemental GINF. (3) High-dose GINF at basal insulin: plasma glucose doubled and synchronous changes in HGP, Rdtissue, MCRg, and GFexog occurred; ICglucose, G6P, and glycogen were unchanged. (4) Hyperglycaemic diabetes: HGP was raised (p < 0.05), matching urinary glucose loss (UGL) and decreased MCRg, and maintaining normal basal Rdtissue and GFexog. SkM ICglucose was increased and glycogen decreased (both p < 0.05). (5) Phlorizin-induced normoglycaemia in diabetic dogs: HGP rose, matching the increased UGL, while maintaining normal Rdtissue and GFexog. Intramuscular substrates normalised. (6) Whole body and SkM metabolism normalised with correction of the insulin resistance and good diabetic control. Conclusion HGP reflects whether SkM is in a state of relative glucose ,excess' or absolute/relative glucose ,deprivation'. Copyright © 2005 John Wiley & Sons, Ltd. [source] Decreased cortisol production in male type 1 diabetic patientsEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 7 2003M. N. Kerstens Abstract Background It is unclear whether cortisol production and the 11,HSD-mediated cortisol to cortisone interconversion are different between type 1 diabetic patients and healthy subjects. Materials and methods Fourteen male, nonobese, normotensive type 1 diabetic patients without severe complications (HbA1c < 8·5%) were studied twice during a daily sodium intake of 50 and 200 mmol, and were then compared with 14 individually matched healthy subjects. Cortisol production was assessed by the sum of urinary cortisol metabolite excretion. Urinary ratios of (tetrahydrocortisol + allo-tetrahydrocortisol)/tetrahydro-cortisone [(THF + allo-THF)/THE] and of free cortisol/free cortisone [UFF/UFE] were determined as parameters of 11,HSD activity. Results Sum of urinary cortisol metabolite excretion during low- and high-salt diet was 7·4 ± 2·5 vs. 7·7 ± 2·3 nmol min,1 m,2 (NS) in diabetic patients and 9·7 ± 2·1 vs. 11·2 ± 4·1 nmol min,1 m,2 (NS) in healthy subjects, respectively (P < 0·05 vs. healthy subjects at both diets). The allo-THF excretion and allo-THF/THF ratios were lower in the diabetic than in the healthy males during both diets (P < 0·05). Urinary (THF + alloTHF)/THE and UFF/UFE were similar in both groups and remained unchanged after salt loading. Conclusions The sum of urinary cortisol metabolite excretion as a measure of cortisol production is lower in nonobese, normotensive type 1 diabetic males with adequate glycaemic control and without severe complications, irrespective of sodium intake. We suggest that this is at least in part as result of diminished 5, reductase activity, resulting in a decreased cortisol metabolic clearance. In type 1 diabetic and in healthy males, the 11,HSD setpoint is not affected by physiological variations in sodium intake. [source] Population pharmacokinetics of ketanserin in pre-eclamptic patients and its association with antihypertensive responseFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 5 2005Lidwien M. Hanff Abstract Ketanserin is an antihypertensive drug that is increasingly being used parenterally in the treatment of pre-eclampsia. Because of lack of efficacy in a substantial part of our pre-eclamptic patients, we determined the plasma concentrations of ketanserin in 51 pre-eclamptic patients. Population pharmacokinetic parameters were assessed using the iterative two-stage Bayesian population procedure. The influence of individual pharmacokinetic parameters on antihypertensive response, expressed as the attainment of a diastolic blood pressure ,90 mmHg using ketanserin treatment, was analysed. Almost all plasma concentrations of ketanserin were in or above the therapeutic range. The individual pharmacokinetics of ketanserin in pre-eclamptic patients showed an accurate fit using a three-compartment model. The pharmacokinetic parameters in our pre-eclamptic population were a metabolic clearance (Clm) of 37.9 ± 10.86 L/h and volume of distribution (V1) of 0.544 ± 0.188 L/kg, which is comparable with data from healthy volunteers. Despite a considerable inter-individual variation, no correlation was found between differences in pharmacokinetic parameters and antihypertensive response. We conclude that therapeutic plasma levels can be obtained in pre-eclamptic patients with a fixed dosage schedule of ketanserin and differences in antihypertensive responses within a pre-eclamptic population cannot be attributed to pharmacokinetic differences. [source] Influence of CYP2C9 and CYP2C19 genetic polymorphisms on pharmacokinetics and pharmacodynamics of gliclazide in healthy Chinese Han volunteersJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 3 2010H. Shao PhD Summary Background and objective:,CYP2C9 is the major contributor to gliclazide metabolic clearance in vitro, while the pharmacokinetics of gliclazide modified release are affected mainly by CYP2C19 genetic polymorphisms in vivo. This study aims to investigate the influence of CYP2C9 and CYP2C19 genetic polymorphisms on the pharmacokinetics and pharmacodynamics of gliclazide in healthy Chinese Han volunteers. Methods:, Eighteen healthy Han subjects with various combinations of CYP2C9 and CYP2C19 genotypes received 80 mg gliclazide. Plasma gliclazide concentrations were measured by a liquid chromatography,tandem mass spectrometry method for 84 h and plasma glucose and insulin levels were measured up to 15 h post-dose. Results and discussion:, There was no difference in either pharmacokinetic and or pharmacodynamic parameters of gliclazide when group A (CYP2C9*1/*1, CYP2C19 extensive metabolizers) was compared with group B (CYP2C9*1/*3, CYP2C19 *1/*1). When group C (CYP2C9*1/*1 and CYP2C19 poor metabolizers) was compared with group A, the AUC0,, and Cmax in group C were significantly higher [83·94 ± 40·41 vs. 16·39 ± 5·10 ,g·h/mL (P = 0·000) and 1·50 ± 0·85 vs. 0·45 ± 0·18 ,g/mL (P = 0·000)], and the oral clearance was significantly lower [1·17 ± 0·63 vs. 5·38 ± 1·86 L/h (P = 0·000)]. The half-life of gliclazide was also significantly prolonged in group C subjects when compared with that of group A (33·47 ± 12·39 vs. 19·34 ± 10·45 h), but the difference was not significant (P = 0·052). The increase in serum glucose level at 11 h after dosing (,Cglu11) in group C was significantly higher than that of group A (,1·08 ± 0·42 vs. 0·22 ± 1·01 mmol/L, P = 0·022). The corresponding insulin levels showed no difference between the two groups. Conclusion:,CYP2C9*3 was not associated with any change in the disposition of gliclazide. CYP2C19 polymorphisms appear to exert the dominant influence on the pharmacokinetics of gliclazide in healthy Chinese Han subjects, and may also affect the observed pharmacodynamics of the drug as a result. [source] Prediction of human pharmacokinetics , improving microsome-based predictions of hepatic metabolic clearanceJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 10 2007Urban Fagerholm Physiologically based methods generally perform poorly in predicting in-vivo hepatic CL (CLH) from intrinsic clearance (CLint) in microsomes in-vitro and unbound fraction in blood (fu,bl). Various strategies to improve the predictability have been developed, and inclusion of an empirical scaling factor (SF) seems to give the best results. This investigation was undertaken to evaluate this methodology and to find ways to improve it further. The work was based on a diverse data set taken from Ito and Houston (2005). Another objective was to evaluate whether rationalization of CLH predictions can be made by replacing blood/plasma-concentration ratio (Cbl/Cpl) measurements with SFs. There were apparently no or weak correlations between prediction errors and lipophilicity, permeability (compounds with low permeability missing in the data set) and main metabolizing CYP450s. The use of CLint class (high/low) and drug class (acid/base/neutral) SFs (the CD-SF method) gives improved and reasonable predictions: 1.3-fold median error (an accurate prediction has a 1-fold error), 76% within 2-fold-error, and a median absolute rank ordering error of 2 for CLH (n = 29). This approach is better than the method with a single SF. Mean (P < 0.05) and median errors, fraction within certain error ranges, higher percentage with most accurate predictions, and ranking were all better, and 76% of predictions were more accurate with this new method. Results are particularly good for bases, which generally have higher CLH and the potential to be incorrectly selected/rejected as candidate drugs. Reasonable predictions of fu,bl can be made from plasma fu (fu,pl) and empirical blood cell binding SFs (B-SFs; 1 for low fu,pl acids; 0.62 for other substances). Mean and median fu,bl prediction errors are negligible. The use of the CD-SF method with predicted fu,bl (the BCD-SF method) also gives improved and reasonable results (1.4-fold median error; 66% within 2-fold-error; median absolute rank ordering error = 1). This new empirical approach seems sufficiently good for use during the early screening; it gives reasonable estimates of CLH and good ranking, which allows replacement of Cbl/Cpl measurements by a simple equation. [source] Prediction of human oral pharmacokinetics using nonclinical data: examples involving four proprietary compoundsBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 8 2008Aberra Fura Abstract The oral pharmacokinetics (concentration-time profile) of four proprietary compounds in humans were predicted using the Cvss - MRT method. The first step was to demonstrate superposition of intravenous (i.v.) pharmacokinetic profiles of preclinical species following mathematical transformation of their respective concentration-time curves using the corresponding Cvss (where Cvss=dose/Vss; Vss is the volume of distribution at steady state) and mean residence time (MRT) values. The resultant profiles were then back-transformed to estimate human i.v. plasma concentration-time profiles using human Cvss and MRT values. Human Cvss and MRT values were estimated from projected human Vss and CL values. Projection of CL was based on scaled (in vitro) metabolic clearance, simple allometry with and without various correction factors and the unbound fraction corrected intercept method. Vss values were estimated by allometric scaling with and without correction for interspecies differences in plasma protein binding. The predicted human i.v. profiles, in combination with the estimated mean absorption rate constants and bioavailability, were then used to simulate the oral pharmacokinetics in human using one- or multi-compartment kinetic models. Overall, with this approach, key oral pharmacokinetic parameters such as AUC, Cmax, Cmin and oral plasma T½ were projected to be within two-fold of the actual values in humans. Copyright © 2008 John Wiley & Sons, Ltd. [source] In Vitro/in Vivo scaling of alprazolam metabolism by CYP3A4 and CYP3A5 in humansBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 2 2001Noriko Hirota Abstract We attempted to predict the in vivo metabolic clearance of alprazolam from in vitro metabolic studies using human liver microsomes and human CYP recombinants. Good correlations were observed between the intrinsic clearance (CLint) for 4-hydroxylation and CYP3A4 content and between the CLint for ,-hydroxylation and CYP3A5 content in ten human liver microsomal samples. Using the recombinant CYP isoforms expressed in insect cells, the CLint for CYP3A4 was about 2-fold higher than the CLint for CYP3A5 in the case of 4-hydroxylation. However, the CLint for CYP3A5 was about 3-fold higher than the CLint for CYP3A4 in the case of ,-hydroxylation. The metabolic rates for 4- and ,-hydroxylation increased as the added amount of cytochrome b5 increased, and their maximum values were 3- to 4-fold higher than those without cytochrome b5. The values of CLint, in vivo predicted from in vitro studies using human liver microsomes and CYP3A4 and CYP3A5 recombinants were within 2.5 times of the observed value calculated from literature data. The average CLint value (sum of 4- and ,-hydroxylation) obtained using three human liver microsomal samples was 4-fold higher than that obtained using three small intestinal microsomal samples from the same donors, indicating the minor contribution of intestinal metabolism to alprazolam disposition. The area under the plasma concentration-time curve (AUC) of alprazolam is reported to increase following co-administration of ketoconazole and the magnitude of the increase predicted from the in vitroKi values and reported pharmacokinetic parameters of ketoconazole was 2.30,2.45, which is close to the value observed in vivo (3.19). A quantitative prediction of the AUC increase by cimetidine was also successful (1.73,1.79 vs 1.58,1.64), considering the active transport of cimetidine into the liver. In conclusion, we have succeeded in carrying out an in vitro/in vivo scaling of alprazolam metabolism using human liver microsomes and human CYP3A4 and CYP3A5 recombinants. Copyright © 2001 John Wiley & Sons, Ltd. [source] The ,apparent clearance' of free phenytoin in elderly vs. younger adultsBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 1 2010Daniel F. B. Wright WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , The clearance of many drugs is reduced in the elderly, but the data regarding phenytoin are conflicting. Most studies have estimated phenytoin metabolic clearance using total drug concentrations (bound plus unbound), which may be confounded by protein binding effects. Free phenytoin concentrations are independent of protein binding and should more accurately reflect true metabolic clearance changes in elderly patients. WHAT THIS STUDY ADDS , The two studies reported in this paper suggest a trend towards reduced free phenytoin ,apparent clearance' in the elderly, although statistically significant results were not found. Other published studies have largely found similar trends, suggesting an age effect. AIMS To test the hypothesis that the ,apparent clearance' of free phenytoin is reduced in elderly patients. METHODS Two separate studies were conducted comparing free phenytoin ,apparent clearance' in elderly vs. younger adults. The first study was a retrospective analysis of free phenytoin concentrations measured at Christchurch Hospital from 1997 to 2006. In the second study free phenytoin concentrations were measured prospectively in ambulatory subjects who were taking phenytoin regularly. RESULTS In the retrospective study (n= 29), free phenytoin ,apparent clearance' was 0.27 ± 0.04 l kg,1 day,1 (95% CI 0.19, 0.34) in the elderly cohort vs. 0.37 ± 0.06 l kg,1 day,1 (95% CI 0.22, 0.52) in younger adults, but the difference was not statistically significant. In the prospective study, free phenytoin ,apparent clearance' showed a non-significant trend to being reduced in the elderly patients (0.12 ± 0.02 l kg,1 day,1, 95% CI 0.07, 0.17) compared with the younger cohort (0.18 ± 0.07 l kg,1 day,1, 95% CI 0.09, 0.26) in those not taking interacting drugs (n= 21). CONCLUSIONS This research does not prove the hypothesis that the ,apparent clearance' of free phenytoin is reduced in the elderly. However, the trends found in these two studies are supported by trends in the same direction in other published studies, suggesting an age effect. [source] Role of valproate across the ages.ACTA NEUROLOGICA SCANDINAVICA, Issue 2006Treatment of epilepsy in the elderly In June 2005, a team of experts participated in a workshop with the objective of reaching agreement on several important aspects of valproate in the treatment of elderly patients with epilepsy. Epilepsy in the elderly is relatively common and its incidence increases for each decade after age 60. The aetiology and manifestations of epilepsies in the elderly are complex because of comorbidity and other underlying risk factors. A consensus was reached that elderly patients who present with a seizure disorder should be referred rapidly to a specialist and that diagnosis should be improved by using a multidisciplinary team of cardiologists, neurologists and epilepsy experts (syncope, falls and seizure specialists). This is especially important to avoid mistreatment with antiepileptic drugs (AEDs). There was consensus that the elderly are generally more susceptible to the adverse effects of AEDs than younger adults. For these reasons, in older persons AEDs should be started at low dosages, and titrated slowly according to clinical response. Some of the most troublesome side effects of AEDs in the elderly include sedation and cognitive side effects, as well as osteoporosis. Drug,drug interactions should be given special consideration. There was consensus that the pharmacokinetics of all AEDs are altered in the elderly, and that the most significant change common to all AEDs is a moderate reduction in renal and metabolic clearance. Predicting pharmacokinetic changes in the individual, however, can be very difficult because multiple factors contribute to a high inter-patient variability. There was agreement on the advantages and disadvantages of the use of valproate in the elderly, and consensus that valproate is a useful option in this population. There was no consensus, however, on whether valproate should be considered among the preferred first-line treatments in the elderly. [source] Stereoselective binding of human serum albuminCHIRALITY, Issue 3 2006Victor Tuan Giam Chuang Abstract Stereoselectivity in binding can have a significant effect on the drug disposition such as first-pass metabolism, metabolic clearance, renal clearance, and protein and tissue binding. Human serum albumin (HSA) is able to stereoselectively bind a great number of various endogenous and exogenous compounds. Various experimental data suggested that the two major drug-binding cavities, namely, site I and site II, do not seem to be the stereoselective binding sites of HSA. Stereoselective binding of HSA under disease conditions such as renal and hepatic diseases was found to be enhanced. In addition, site-to-site displacement of a site II-specific drug by another site II-specific drug was found to be stereoselective, too. Endogenous compounds such as long-chain fatty acids and uremic toxins are likely to cause combined direct and cascade effects that contribute to the preferential binding of a particular drug enantiomer. Taking together the findings of other studies, it is highly possible that the stereoselective binding site exists at the interface of the subdomains. © 2006 Wiley-Liss, Inc. Chirality [source] Cushing's syndrome due to pharmacological interaction in a cystic fibrosis patientACTA PAEDIATRICA, Issue 9 2002KM Main Treatment of allergic bronchopulmonary aspergillosis with itraconazole is becoming more widespread in chronic lung diseases. A considerable number of patients is concomitantly treated with topical or systemic glucocorticoids for anti-inflammatory effect. As azole compounds inhibit cytochrome P450 enzymes such as CYP3A isoforms, they may compromise the metabolic clearance of glucocorticoids, thereby causing serious adverse effects. A patient with cystic fibrosis is reported who developed iatrogenic Cushing's syndrome after long-term treatment with daily doses of 800 mg itraconazole and 1600 ,g budesonide. The patient experienced symptoms of striae, moon-face, increased facial hair growth, mood swings, headaches, weight gain, irregular menstruation despite oral contraceptives and increasing insulin requirement for diabetes mellitus. Endocrine investigations revealed total suppression of spontaneous and stimulated plasma cortisol and adrenocorticotropin. Discontinuation of both drugs led to an improvement in clinical symptoms and recovery of the pituitary-adrenal axis after 3 mo. Conclusion: This observation suggests that the metabolic clearance of budesonide was compromised by itraconazole's inhibition of cytochrome P450 enzymes, especially the CYP3A isoforms, causing an elevation in systemic budesonide concentration. This provoked a complete suppression of the endogenous adrenal function, as well as iatrogenic Cushing's syndrome. Patients on combination therapy of itraconazole and budesonide inhalation should be monitored regularly for adrenal insufficiency. This may be the first indicator of increased systemic exogenous steroid concentration, before clinical signs of Cushing's syndrome emerge. [source] | ||||||||||