摘要:

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 agent

ISSN:0142-2782    

DOI:10.1002/bdd.2510100102

出版商:John Wiley&Sons, Ltd.    

年代:1989

数据来源: WILEY

摘要:

AbstractA size of error in observed data for fitting curves and an estimation problem due to multiple solutions in a two‐compartment model were studied by using two different non‐linear least‐squares regression programs, SALS and NONLIN. It was found that bolus intravenous data have generally 5–10 per cent errors and oral data contain 10–25 per cent errors against the fitted data with respect to total 151 data sets of 11 different drugs. Parameters of five drugs reported in references were used to obtain simulated concentrations at the sampling times, and five different data sets containing 25 per cent normally distributed random errors as a coefficient of variation were generated using each data set of these simulated concentration. In the two‐compartment model with tri‐exponential equations, unreasonable estimates were occasionally observed, resulting in reversed relative values to the theoretical ones ofL/M, L/N, M/NorKa/α, which are analogous to the well‐known flip‐flop phenomenon in the one‐compartment model, when number of parameters to be estimated is not less than five or errors of data exceed about 10 per cent. In an attempt to avoid such unreasonable values, initial estimates for curve fitting was successfully obtained by using a microcomputer program SIMPLEX based on a simplex method. On the basis of these results, some problems in curve fitting of plasma drug concentratio

ISSN:0142-2782    

DOI:10.1002/bdd.2510100103

出版商:John Wiley&Sons, Ltd.    

年代:1989

数据来源: WILEY

摘要:

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 ofKmandVmaxwere 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 proces

ISSN:0142-2782    

DOI:10.1002/bdd.2510100104

出版商:John Wiley&Sons, Ltd.    

年代:1989

数据来源: WILEY

摘要:

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

ISSN:0142-2782    

DOI:10.1002/bdd.2510100105

出版商:John Wiley&Sons, Ltd.    

年代:1989

数据来源: WILEY

摘要:

AbstractAn equation based on the absorption potential concept was developed. This enabled us to establish an approach for the quantitative prediction of the fraction of dose absorbed. Classification of drugs into three broad categories, according to their absorption potential values in relation to the fraction of dose absorbed, was attempted. The new approach was tested using literature data with very good results.

ISSN:0142-2782    

DOI:10.1002/bdd.2510100106

出版商:John Wiley&Sons, Ltd.    

年代:1989

数据来源: WILEY

摘要:

AbstractThe purpose of this study was to dissociate the authentic and artifactual effect ofin vivoheparin on drug protein binding using protamine as an inhibitor ofex vivolipolysis. A mixture of ethylenediamine tetra‐acetic acid (EDTA, 5 mg ml−1) and protamine in the concentration range of 0 to 7·5 mg ml−1was added to blood samples from 23 cardiac catheterized patients before (control) and 10 min after 3000 IU of intravenous heparin. In control samples, protamine does not interfere with the protein binding of lidocaine (L), quinidine (Q) or propranolol (P) when plasma pH is readjusted to 7·4. In the absence of protamine, heparin induced a significant increase in the free fraction by 40, 130, and 30 per cent for L, Q, and P, respectively (p<0·001), while free fatty acid (FFA) levels increased 2 to 6 fold. When protamine was present, the heparin‐induced elevation in free fraction was significantly lower for L (16 per cent) and Q (77 per cent) but not for P; FFA levels were decreased at all protamine concentrations. Residual increases in free fraction and FFA levels compared to control values may represent the truein vivoeffect of heparin at the peak activity of lipoprotein lipases. For L and Q, variations in free fraction were strongly associated with variations in FFA, but for P, no significant correlation was observed (r= 0·492). These results indicate that variations in free fraction of L and Q caused by heparin are, to a large extent, artifactual but may be prevented by use of protamine in collection tubes (5 to 7·5 mg ml−1). For P, the increase in free fraction was not mediated by variations of FFA indicating that another mechanism mu

ISSN:0142-2782    

DOI:10.1002/bdd.2510100107

出版商:John Wiley&Sons, Ltd.    

年代:1989

数据来源: WILEY

摘要:

AbstractTwo multiple dose crossover pharmacokinetic studies were carried out to determine the steady‐state bioavailability of newly formulated generic propranolol HCl tablets relative to Inderal® tablets. In Study I, 24 healthy volunteers were dosed with 4 × 10mg test tablets, 1 × 40 mg test tablet, 4 × 10 mg Inderal tablets, and 40 mg of propranolol HCl in solution. In Study II, 24 healthy volunteers were dosed with 1 × 80 mg test tablet, 1 × 80 mg Inderal tablet, and 80 mg of propranolol HCl in solution. Both studies were of randomized design with each formulation administered every 8h for 15 doses. Serial plasma samples were obtained for 8 h after morning doses on Days 4 and 5 of each treatment period and assayed for propranolol using a validated HPLC method. Mean plasma concentration‐time data for test tablets and reference tablets were superimposable in both studies.Pharmacokinetic parameters from Days 4 and 5 were combined for statistical analysis since subjects were determined to have reached steady‐state. Mean AUC,Cmax,tmax, andCminvalues were not statistically different between test tablets and Inderal tablets in either study. Based on these findings, the test tablets demonstrated the same rate and extent of propranolol absorption as did corresponding Inderal® tablets. Therefore, the test tablets and Inderal® tablets were determined to be

ISSN:0142-2782    

DOI:10.1002/bdd.2510100108

出版商:John Wiley&Sons, Ltd.    

年代:1989

数据来源: WILEY

摘要:

AbstractThe disposition of theophylline was studied on four occasions in eight healthy adult males. The control mean theophylline half‐life and clearance were 7·32 h and 0·86 ml min−1kg−1, respectively. After 5 days pretreatment with placebo the corresponding values of 7·01 and 0·88 were not significantly different, as were those of 7·43 and 0·85 after 5 days pretreatment with ranitidine (1·2g daily). Five days pretreatment with cimetidine (1·0g daily) resulted in a significant 44·4 per cent rise in the mean theophylline half‐life and a 36·1 per cent fall in clearance. The fall in clearance correlated positively (r=0·9407) with the initial value. The volume of distribution did not change significantly throughout the study period. The fact that, at as large a dose as 1·2g daily, ranitidine did not impair theophylline metabolism suggests that similar results reported earlier with therapeutic doses of 300 mg daily cannot be ascribed to the lower dose of ranitidine employed. It is also suggested that the risk of theophylline toxicity consequent on cimetidine coadministration will be more likely in individuals with initial high the

ISSN:0142-2782    

DOI:10.1002/bdd.2510100109

出版商:John Wiley&Sons, Ltd.    

年代:1989

数据来源: WILEY

摘要:

AbstractThe role of the kidneys in the elimination of theophylline was directly assessed using nephrectomized dogs. Data was analyzed by two different pharmacokinetic approaches. Analysis indicated that a given dosage regimen produced significantly different serum concentrations before and after nephrectomy. Model independent pharmacokinetic analysis failed to show a significant difference in parameters. A model dependent approach, using a nonlinear regression analysis employing a linear two‐compartment model, demonstrated that the differences observed could be accounted for by a change in the first order elimination kinetic

ISSN:0142-2782    

DOI:10.1002/bdd.2510100110

出版商:John Wiley&Sons, Ltd.    

年代:1989

数据来源: WILEY

ISSN:0142-2782    

DOI:10.1002/bdd.2510100111

出版商:John Wiley&Sons, Ltd.    

年代:1989

数据来源: WILEY