bluuebunny/crossref_metadata_2025_split huggingface dataset:
Importance of analytical methods in pharmacokinetic and drug metabolism studies
Authors: Hirtz J. 
Published: October 2006

AbstractPharmacokinetic and drug metabolism studies first request that good analytical data are available. The various methods that permit unchanged drugs and their metabolites to be separated, identified and quantitatively assayed are briefly reviewed. The present importance of gas chromatography/mass spectrometry is emphasized, as well as the limits of immunological assays. The sensitivity of the analytical assay has a direct impact on the validity of the pharmacokinetic model which is built up from plasma concentration data. The precision and accuracy of the assay is also critical, and it is not always easily estimated. A new significant parameter is the speed of analysis, and the resulting massive production of analytical data. New drugs coming from biotechnology, and new dosage forms, like targeted drugs, will create new analytical problems in the future. They will probably call for the development of new biological or pharmacological assay procedures, in addition to the physicochemical means of analysis.
Plasma concentrations and relative bioavailability of naftidrofuryl from different salt forms
Authors: Walmsley L. M. , Taylor T. , Wilkinson P. A. , Brodie R. R. , Chasseaud L. F. , Alun‐Jones V. , Hunter J. O. 
Published: October 2006

AbstractThe relative bioavailability of the vasodilator naftidrofuryl from formulations containing its oxalate or citrate salt has been estimated using a specific HPLC assay, and a less specific fluorimetric assay, to measure plasma drug concentrations. The conclusions of the study were the same irrespective of the assay employed. The relative rate, but not the extent, of bioavailability of naftidrofuryl from the citrate salt (peak 1096 ng ml−1 at 0·76 h) was marginally greater (p = 0·003) than that from the oxalate salt (peak 922ng ml−1 at 0·94 h). The degree of intersubject variability was similar after administration of either salt form. The mean half‐life of naftidrofuryl was 1·8 h and its mean residence time was 2·5 h.
Ceforanide pharmacokinetics in haemodialysis: The effect of ultrafiltration
Authors: Lanao José M. , De Prada Consuelo R. , Dominguez‐Gil Alfonso , Tabernero José M. , Martín Jesús , Gómez Juan R. 
Published: October 2006

AbstractThe kinetics of ceforanide in plasma and dialysate was studied in 8 patients with terminal renal impairment after undergoing haemodialysis sessions lasting between 4 and 5 h. All patients received a single i.v. dose of 15 mg kg−1 of the drug at the start of the session. The dialysers used in this study were Spiraflow capillar 1·3 m2, Travenol plates 1·4 m2, and PAN plates. Blood flow ranged between 200 and 300 ml min−1 and dialysate flow between 500–650 ml min−1. Plasma ceforanide levels were measured at the input and output of the dialyser and the antibiotic levels in dialysate were determined coinciding with the withdrawal times of the blood samples. A microbiologic plate diffusion method was used to determine the antibiotic concentrations.The mean values of some pharmacokinetic parameters of ceforanide calculated with a non‐linear regression program from the data obtained from arterial blood were the following: α (h−1) = 4·14 ± 1·32; β (h−1) = 0·26 ± 0·07; t1/2 β (h) = 2·82 ± 0·82; Vdss (1) = 10·24 ± 2·14.From the relationships between the antibiotic concentrations at the input and output of the dialyser it was possible to calculate an extraction coeffficient of 0·11 ± 0·06. The dialysis clearance of ceforanide was calculated from the determination of the extraction coefficient and from the measuring of antibiotic in dialysate, though different results were obtained with the two methods. Dialysis clearance calculated from the extraction coefficient showed a mean value of 18·68 ± 12·16 ml min−1, significantly lower (p < 0·01) than that established by analysis of the antibiotic in dialysate, which was 41·55 ± 15·83 ml min−. These differences may be attributed to problems related to the determination of blood flow and to the ultrafiltration capacity of the dialysis membranes. A linear relationship was established between the percentage error in the observed and predicted extraction coefficients and the ultrafiltration rate. The results obtained suggest that the simultaneous measurement of the antibiotic in plasma and dialyate is the most suitable method for predicting the dialysis clearance of the drug. The amount of antibiotic extracted over a 4‐hour dialysis session proved to be equal to 57·85 ± 15·62 per cent of the dose administered.
Renal and non‐renal clearances of iothalamate
Authors: Prueksaritanont Thomayant , Lui Chung Y. , Lee Myung G. , Chiou Win L. 
Published: October 2006

AbstractAn evaluation of the literature indicated that certain aspects of the disposition kinetics of iothalamate, important to the accurate determination of glomerular filtration rate in dogs and humans, remain to be resolved. The simultaneous clearances of iothalamate and inulin in 5 dogs were determined at three steady‐state iothalamate plasma levels (2, 10, and 40μg ml−1) following various rates of intravenous infusion. The iothalamate clearances, both renal and non‐renal, were concentration‐independent. The overall mean non‐renal clearance was 18 per cent (ranging from 9 to 25 per cent) of its plasma clearance. The mean iothalamate/inulin renal clearance ratio was about 0·84 with individual values ranging from 0·72 to 0·95. The significant (4–26 per cent) plasma protein binding of iothalamate in these dogs was the main reason for the lower‐than‐unity clearance ratios obtained. The literature indicates the existence of up to 25 per cent of non‐renal elimination in humans with normal renal function; this is comparable to the present results obtained with dogs but contrary to the assumption, sometimes reported in the literature that non‐renal elimination is essentially absent in humans. Binding of iothalamate to plasma proteins from humans was not found in the present study. The above results suggest that for accurate glomerular filtration rate determination in humans and dogs, especially for those with renal impairment, renal clearance rather than plasma clearance should be used, and in the case of dogs it should also be corrected for plasma protein binding. Iothalamate in plasma and urine was analysed by a simple, micro high‐performance liquid chromatographic method with UV detection.
Pharmacokinetics of insulin following intravenous and subcutaneous administration in canines
Authors: Ravis William R. , Comerci Carol , Ganjam Ventateseshu K. 
Published: October 2006

AbstractStudies were conducted to examine the absorption and disposition kinetics of insulin in dogs following intravenous (IV) and subcutaneous (SC) administration of commercial preparations. After IV and SC dosing, the plasma levels were described by models which considered basal insulin level contributions. Intersubject variation in the disposition kinetics was small with half‐lives of 0.52 ± 0.05 h and total body clearances of 16.21 ± 2.08ml min−1kg−1. Calculated insulin plasma secretion rates in the canines were 14.4 ± 3.3 mUh−1kg−1. Following SC injection of regular insulin, the rate and extent of absorption were noted to be quite variable. The absorption process appeared first‐order with half‐life values of 2.3 ± 1.3 h and extents of absorption of 78 ± 15 per cent with a range of 55–101 per cent. Insulin absorption from SC NPH preparations was evaluated as being composed of two zero‐order release phases, a rapid and a slow release phase. With a dose of 1.65 U kg−1, the rapid release phase had an average duration of 1.5 h and a rate of 580 ± 269 mU h−1(4.2 per cent of dose) while the slow phase had a zero‐order rate of 237 ± 92mU h−1which continued beyond 12h. The extent of absorption from the NPH preparation was 23.6 ± 5.1 per cent and was significantly lower than that for the regular injection.
Time‐dependent inhibition of theophylline elimination by erythromycin stearate
Authors: Adebayo G. I. , Adewumi M. O. , Mabadeje A. F. B. 
Published: October 2006

AbstractThe effect of erythromycin stearate at a dose of 1 g daily on theophylline disposition was studied in six healthy adult males. The mean value of 5·46 h for the theophylline half‐life after 48 h pretreatment with erythromycin stearate was not significantly different from the control value of 5·24h. The half‐life value of 8·48 h after a 1‐week course of the antibiotic, however, represented a significant increase (p < 0·005). Theophylline disposition 1 week after the last dose of the antibiotic was not significantly different from the control. It is suggested that therapeutic doses of erythromycin stearate for a week or more could impair the disposition of concurrently administered theophylline. The impairment however, is reversible, being absent a week after the last antibiotic dose.
Effect of intravenous infusion time on the pharmacokinetics and pharmacodynamics of the same total dose of furosemide
Authors: Lee Myung G. , Li Tun , Chiou Win L. 
Published: October 2006

AbstractThe pharmacokinetics and pharmacodynamics of furosemide were evaluated after intravenous administration of the same total dose of furosemide in different lengths of infusion time (10s, 30 min, 2h, and 8h) to 6 dogs. The fluid loss in urine was immediately replaced volume for volume with intravenous infusion of Lactated Ringer's solution. The pharmacokinetic parameters such as per cent of the dose excreted in urine, total body and renal clearances, and terminal half‐life were not significantly different with four different infusion times. The volume of distribution at steady state and mean residence time based on venous data, on the other hand, appeared to increase with increasing infusion time. The mean values for Vss were 0·334, 0·478, 0·499, and 0·708 1 kg−1 for 10s, 30 min, 2h, and 8h of infusion, respectively, and the corresponding values for MRT were 17·5, 22·2, 24·8, and 38·1 min. The diuretic effects (urine output and urinary excretion of sodium) were generally found to increase with increasing infusion times; the total mean 24h urine outputs were 1102, 1464, 2190, and 3470 ml for 10 s, 30 min, 2h, and 8h of infusion, respectively, and the corresponding values for sodium excretion were 170, 175, 272, and 440 mmol. Furosemide plasma concentrations and hourly urinary excretion rates of furosemide, sodium, and potassium during the apparent steady state (between 2 and 8h) in the 8h infusion study were fairly constant.
Correlation between inhibitory effect on platelet aggregation and disposition of sulfinpyrazone and its metabolites in rabbits. Part II: Multiple dose study
Authors: Kuo Be‐Sheng , Ritschel Wolfgang A. 
Published: October 2006

AbstractIn a crossover study rabbits were given perorally sulfinpyrazone (SO) and the sulfide metabolite (S) every 24h for 5 days on separate occasions and inhibition of aggregation was measured. The results showed: (1) the dosage regimen is effective if the minimum effective concentration of S is defined to be between 0.5–1.0μg ml−1 and (2) the repeated dosing did not cause changes in disposition kinetics except that the terminal half‐life of S was reduced after dosing with S. No significant accumulations in trough concentration and inhibition of aggregation were observed. The results obtained in this study could provide some useful information for design of dosage regimen and blood level monitoring for humans.
Sulfamethazine absorption and disposition: Effect of surgical procedures for gastroduodenal ulcers
Authors: Calvo Rosario , Sarabia Sebastian , Carlos Raimundo , Souich Patrick Du 
Published: October 2006

AbstractThis study was designed to determine whether the surgical procedures for gastroduodenal ulcers influence sulfamethazine (SMZ) absorption and disposition. Prior to and on the average 79 days after surgery, eight patients received 10mg kg−1 of sulfamethazine orally. Blood samles were obtained at regular intervals over 24h and urine was collected for 48h. Vagotomy with pyloroplasty or with gastrojejunostomy had no effect on SMZ kinetics. Vagotomy with partial gastrectomy decreased the SMZ plasma peak concentrations from 43.9 ± 7.1 (mean ± SEM) to 17.2 ± 5.2 μg ml−1 (p < 0.05) and increased the time required to reach this peak from 2.6 ± 0.8 to 9.8 ± 2.8 h (p < 0.05). SMZ rate constant of absorption decreased only slightly (1.22 ± 0.45 to 0.24 ± 0.07 h−1) and SMZ bioavailability was not affected at all. In two (out of four) patients, SMZ volume of distribution and total body clearance increased, as reflected in the 41 per cent decrease in the mean area under the SMZ plasma concentration–time curve. No changes were detected in SMZ protein binding. Computer simulations indicated that in some subjects SMZ plasma concentrations at steady state could be 76 per cent lower following vagotomy with partial gastrectomy than before surgery. It was concluded that vagotomy and antrectomy with a gastroduodenostomy or Billroth I reconstruction decreased the rate of SMZ absorption and only in some subjects increased the SMZ volume of distribution and rate of elimination. The possible mechanisms involved in these reported kinetic changes are discussed.
Cimetidine inhibition of theophylline elimination: The influence of adult age and the time course
Authors: Adebayo G. I. , Coker H. A. B. 
Published: October 2006

AbstractThe effect of placebo or cimetidine at a dose of 1 g daily on theophylline elimination was studied in a double‐blind control manner in twelve healthy adult males aged 19–31 years. In a group of six, placebo had no effect on any of theophylline half‐life (t1/2), volume of distribution (Vd), and total body clearance (CL). In another group of six, theophylline t1/2 rose significantly from 5.48 to 9.04 h (p < 0.001) after 48 h and to 8.98 h (p < 0.001) after a week pretreatment with cimetidine. Correspondingly, CL (ml min−1kg−1) fell to 0.66 (p < 0.025) and 0.60 (p < 0.01). Changes after 48h pretreatment were not different from those after a week pretreatment. Seven days after the last cimetidine dose, theophylline disposition had reverted to the control level. There was no significant change in Vd. In five elderly subjects aged 56–68 years, a week of dosing with cimetidine caused a rise in t1/2 (7.17 h to 10.39 h; p < 0.001) and a fall in CL (0.77 ml min−1kg−1 to 0.53 ml min−1kg−1; p < 0.005) without significantly altering Vd. In two subjects, there was restoration of theophylline disposition to the control level 72 h after cessation of cimetidine intake. Changes in the elderly were not significantly different from those in the younger ones.Data indicate that cimetidine–induced impairment of theophylline disposition is of rapid onset, has rapidly attainable maximum effect, and is rapidly reversible. Furthermore elderly individuals are just as susceptible to it as the younger adults.
Drug absorption evaluation in the presence of changes in clearance: An gorithm and computer program for deconvolution with exact clearance correction
Authors: Veng‐Pedersen Peter 
Published: October 2006

AbstractMost commonly drug absorption is evaluated with a reference dosing given on separate occasions. The assumption that no change in drug disposition is taking place between the drug administrations is often violated resulting in errors in the calculations. A novel deconvolution method is presented which exactly compensates for a change in drug clearance. The method is based on a model independent disposition decomposition‐recomposition technique. The distribution function is obtained from an i.v. administration by disposition decomposition. This distribution function is assembled together with the elimination kinetics containing the perturbed clearance to construct the perturbed disposition function in the subsequent disposition recomposition operation. The perturbed absorption response is finally deconvolved using the corresponding perturbed disposition function. It is shown that the perturbed clearance can be obtained from the log‐linear terminal disposition phase once the distribution function has been obtained from an i.v. administration. The proposed method is implemented in an algorithm and computer program DCONB and demonstrated using human cimetidine drug level data from an i.v. and oral administration. The usage of DCONB is identical to DECONV previously published. It requires only regular sums of exponentials to be fitted to drug level data. Such fittings are routinely done in pharmacokinetics thereby enabling DCONB to be implemented very simply.
Pharmacokinetic and pharmacodynamic studies of felodipine in healthy subjects after various single, oral and intravenous doses
Authors: Edgar Boo , Regårdh Carl G. , Lundborg Per , Romare SÖRen , Nyberg Gunnar , Rönn Ola 
Published: October 2006

AbstractThe objective of this single‐dose study was to evaluate the pharmacokinetics and haemodynamic changes in healthy male subjects following the administration of three oral (5, 15, and 40 mg) and two intravenous (1 and 3 mg) doses of felodipine, a new calcium antagonist with a selective effect on the peripheral resistance vessels.Felodipine was rapidly absorbed within 1 h when administered as an oral solution, but underwent extensive presystemic elimination. The systemic availability varied between 10 and 23 per cent. The disposition was adequately described by a two‐compartment model: the disposition was essentially dose‐independent up to 40 mg orally and 3 mg intravenously.Felodipine produced significant dose‐dependent reduction of diastolic blood pressure and a significant reflexogenic increase in heart rate, without having any major effect on systolic blood pressure. These changes indicate that felodipine acts predominantly as an arteriodilator. The decrease in diastolic blood pressure and increase in heart rate were closely correlated with the plasma concentrations of unchanged felodipine, being maximal at 0.5 h and lasting for at least 4 h after the highest dose.
Theophylline tissue partitioning and volume of distribution in normal and dietary‐induced obese rats
Authors: Shum Linyee , Jusko William J. 
Published: October 2006

AbstractTheophylline tissue distribution was examined in normal and dietary‐induced obese Sprague‐Dawley rats following constant infusion to steady‐state. Theophylline distribution was linear among all tissues and uniform throughout body water spaces. The apparent distribution coefficient, Kd,app (tissue: serum concentration) ranged from 0.55 to 0.69 for all lean tissues, but averaged 0.08 in fat. Obese rats had a consistently higher Kd,app in several tissues including muscle, heart, and liver caused by reduced (from 42 to 33 per cent) serum protein binding. Muscle slice uptake of theophylline from buffer was similar in normal and obese animals, confirming serum binding as the factor altering Kd,app. The conceptual and applied bases of calculating and measuring steady‐state volume of distribution (Vss) by various methods were explored. The physiological perturbations of theophylline Vss by obesity can be accounted for by alterations in serum binding and expanded lean and fat tissue masses, rather than changes in tissue partitioning.
Single‐dose pharmacokinetics and bioavailability of famotidine in man. Results of multicenter collaborative studies
Authors: Yeh K. C. , Chremos A. N. , Lin J. H. , Constanzer M. L. , Kanovsky S. M. , Hucker H. B. , Antonello J. , Vlasses P. , Ryan J. R. , Williams R. L. 
Published: October 2006

AbstractPharmacokinetics and bioavailability of famotidine, a new H2‐receptor antagonist, were investigated in healthy subjects in five clinical studies. Linear pharmacokinetics were observed following either intravenous or oral administration. Plasma clearance averaged 463 ml min−1. Renal clearance averaged 310 ml min−1, which exceeded the glomerular filtration rate. Renal excretion was the major route of elimination. Urinary recovery of unchanged drug following intravenous administration was about 67 per cent. Famotidine plasma half‐life was approximately 2.6h. Oral absorption was incomplete. The bioavailability averaged 43 per cent of the dose.
Pharmacokinetics of non‐prescription sympathomimetic agents
Authors: Chua S. S. , Benrimoj S. I. , Triggs E. J. 
Published: October 2006

AbstractThe pharmacokinetics of non‐prescription sympathomimetic agents are discussed with respect to absorption from the gastrointestinal tract, volumes of distribution, metabolism and renal excretion. Where specific data are not available, postulations are made with inference from the chemical structures of these agents, or from studies with other drugs. No studies on hypertensive patients have been found, but attempts are made to correlate any possible changes in the pharmacokinetics of these sympathomimetic agents to hypertensive patients as a high proportion of the elderly population is hypertensive. Sympathomimetic agents with lesser polar hydroxl groups, for example, are thought to be more lipophilic and are more readily absorbed from the gastrointestinal tract, have higher volumes of distribution, and are more extensively metabolized. Major metabolic pathways include oxidation, deamination, demethylation, and conjugation. Most of these agents are excreted primarily through the kidneys and due to their basic nature, the rate of excretion is dependent on urinary pHs. Any alteration in kidney functions such as in the aged is, therefore, expected to have some clinical significance on the pharmacokinetics of these agents.
Nonlinear least‐squares regression analysis by a simplex method using differential equations containing michaelis‐menten type rate constants
Authors: Murata Kazuo , Kohno Keiichi 
Published: October 2006

AbstractComputer curve fittings were carried out to observed data as well as theoretically generated plasma concentrations of several drugs, using differential equations which contained nonlinear Michaelis‐Menten type rate constants to discuss problems of initial parameter estimation in pharmacokinetic analysis. Calculation based on two different algorithms, each carried out by using SIMP (simplex method) and NONLIN (modified Gauss‐Newton method) produced similar results. However, occasional divergence or unreasonable solutions occurred in a later case, when assumed values of Km and Vmax were used as initial parameters. A combined use of SIMP and NONLIN in which calculated values by SIMP were used as initial values for NONLIN, was shown to be effective to analyse plasma concentration data of indocyanine green bearing difficulty in estimating initial values. It is suggested that the successive method is useful for the curve fitting of plasma concentration with nonlinear pharmacokinetic rate processes.
Effect of bupropion on cimetidine and ranitidine absorption in rats
Authors: Tanira Musbah O. M. , Kaka Juzar S. , Al‐Khamis Khalil I. 
Published: October 2006

AbstractCimetidine and ranitidine absorption were studied in rats, alone or in combination with concurrent but separate bupropion oral admininstration. Blood samples were collected before and 0·25, 0·5, 0·75, 1·0, 1·5, 2·0, 3·0, 4·5, and 6·0h after dosing. In ranitidinetreated rats, an exta blood sample at 8h was collected. Assays of cimetidine and ranitidine were carried out using a HPLC method. Mean cimetidine plasma concentrations on concurrent bupropion administration at 0·25 and 0·5 h were approximately 2 and 1·5 times compared to the control. Similarly, mean ranitidine plasma concentrations with bupropion combination at 0·25 and 0·5 h were significantly different and approximately 2 and 3 times higher. Time of maximum concentration for cimetidine and ranitidine on combination were reduced to almost half of the control value. However, only the time of maximum concentration for cimetidine showed statistically significant difference. No significant differences were observed between AUCs, maximum concentrations, and half‐lives of cimetidine and ranitidine compared to their respective controls. The results suggest that concurrent bupropion admininstration may affect the rate but not the extent of absorption of cimetidine and ranitidine.