摘要:

AbstractThe microsomal mixed function oxidase system contains the cytochrome P‐450 oxidative drug metabolizing family of enzymes. The catalytic cycle of cytochrome P‐450 is believed to involve the formation of an active iron‐oxygen species which is responsible for oxygen transfer to the substrate. This assumption is supported by the fact that a number of peroxidative agents can replace NADPH, the reductase, and oxygen as co‐reactants in most oxidative reactions of microsomal cytochrome P‐450. We have found that a mixture of either ferrous or ferric ions with hydrogen peroxide (Fenton and Ruff reagents) can serve as biomimetic models for cytochrome P‐450 in hydroxylation, exposidation, sulfoxidation, and N‐demethylation of various drugs. The existance of an iron‐oxo active species in both Fenton and Ruff type reactions has been postulated and provides reaction cycles similar to those of cytochrome p‐450.Other model systems for the hepatic hydroxylation and epoxidation using transition metal complexes with porphyrin are also discussed.The present paper reviews the various biomimetic models of the heme cytochrome P‐450 and emphasizes their simulation of hepatic drug metabolism and their potential medical and indu

ISSN:0142-2782    

DOI:10.1002/bdd.2510100502

出版商:John Wiley&Sons, Ltd.    

年代:1989

数据来源: WILEY

摘要:

AbstractThe correct use of probability distribution functions is described for the determination of mean residence time (MRT) of drug molecules in the body and is illustrated for two possible two compartment body models. A new method for estimating (MRT) is described, based on the area under the curve measurement for the decay of drug from steady state.

ISSN:0142-2782    

DOI:10.1002/bdd.2510100503

出版商:John Wiley&Sons, Ltd.    

年代:1989

数据来源: WILEY

摘要:

AbstractThe pharmacokinetics of methylprednisolone and methylprednisolone phosphate were investigated after intravenous administration of methylprednisolone phosphate to six healthy subjects at seven different doses between 16 and 1000 mg. Plasma, urine, and saliva were analyzed for methylprednisolone and methylprednisolone phosphate. Furthermore, endogenous hydrocortisone was measured in plasma. No non‐linearity in the total body clearance of methylprednisolone phosphate or methylprednisolone could be detected. The average elimination half‐life for the prodrug was 3·7 min indicating rapid hydrolysis. After 15 min more than 90 per cent of the phosphate has been hydrolyzed. No prodrug could be detected in saliva; very little of the ester (average 0·9 per cent of the dose) was excreted unchanged into the urine. Methylprednisolone is formed rapidly. The total body clearance was 21 1h−1, the terminal half‐life 2·8 h. In the post‐distribution phase methylprednisolone levels in saliva went parallel to plasma levels. The mean saliva/plasma ratio was 0·22. An average of 5·2 per cent of the dose was eliminated into the urine in the form of methylprednisolone. Hydrocortisone suppression was dosedependent. For doses above 125 mg hydrocortisone levels were significantly lowered after 24 h. For doses above 500 mg the suppression was still significant after 48 h. The results indicate a rapid and predictablein vivoconversion of methylprednisolone phosphate to its active form meth

ISSN:0142-2782    

DOI:10.1002/bdd.2510100504

出版商:John Wiley&Sons, Ltd.    

年代:1989

数据来源: WILEY

摘要:

AbstractThe protein binding of sulfamethazine (SMZ) was studied in rabbit serum. Serum solutions comprising various concentrations (∼0·01 – 3mM) of SMZ and its major metabolite, N4‐acetylsulfamethazinc (AcSMZ), were prepared. These ‘control’ samples were also mixed via a Latin square design to study the interactive binding of SMZ and AcSMZ to the proteins. Equilibrium dialysis was conducted for 8 h.Post‐dialysis measurement of SMZ/AcSMZ radioactivity in the buffer and serum chambers provided the free and bound fractions based upon equilibrium total serum concentrations. There was no significant change of protein concentration before and after dialysis. The ‘control’ data revealed concentration‐dependent binding for both drugs while the interaction study clearly indicated the presence of competitive binding. Scatchard plots suggested the presence of more than one binding site. As a result, three different competitive binding models were examined via computer analysis of the observations. The most appropriate binding model was identified to consist of specific binding (protein concentration,Pt; dissociation constant,Kd) and nonspecific binding (Nsp). The mean (SD) ‘control’ parameter estimates forPtSMZ,PtAcSMZ,KdSMZ,KdAcSMZ,NspSMZ,NspAcSMZwere: 0·562(0·041), 0·605(0·024), 0·078(0·006), 0·031(0·002) [mM], 0·205(0·054), and 0·229(0·043), respectively. In the interaction study these values were: 0·599(0·022), 0·479(0·019), 0·091(0·004), 0·023(0·001), 0·228(0·020), and 0·434(0·061), respectively. The findings indicate that both drugs bind to albumin but the affinity of AcSMZ is greater than SMZ. Theoretically, the metabolite can therefore alter thein vivoSMZ binding thereby in turn causing apparent nonlinear acetylation based upon th

ISSN:0142-2782    

DOI:10.1002/bdd.2510100505

出版商:John Wiley&Sons, Ltd.    

年代:1989

数据来源: WILEY

摘要:

AbstractWe studied the steady‐state disposition of slow release theophylline tablets and granules in 12 institutionalized (I) and 12 community‐dwelling (C) elderly patients with fixed chronic obstructive lung disease. Design was open label with random order crossover; each formulation was given 5 min before food every 12h for 7 days. Age (median 70y, range 55–88), sex, smoking status, and baseline lung function off drug were similar. Trough plasma concentration (Cp) was higher with the tablets as was the area under theCp vs time curve: 134 (74–252) vs 121 (75–197) mghl−1;p=0·028. The standard deviation ofCp over one dose interval was lower with the granules. FEV1·0 was slightly improved over baseline. Dose required to reach targetCp was higher in the institutionalized group (12·6 vs 8·6mg kg−1day−1;p=0·003) as was apparent clearance; I:94 (43–148) ml hr−1kg−1vs C:68 (34–163);p=0·003. Although biovailability was slightly reduced for the granules, fluctuations ofCp was less, and we failed to find a food effect that was clinically im

ISSN:0142-2782    

DOI:10.1002/bdd.2510100506

出版商:John Wiley&Sons, Ltd.    

年代:1989

数据来源: WILEY

摘要:

AbstractTwo nonlinear pharmacokinetic models were simulated to investigate the relationship between single and multiple dose bioequivalency parameters for drugs such as phenytoin and propranolol which exhibit either saturable elimination kinetics or a capacity limited first pass effect. Mean Tmax, Cmaxand area under the plasma‐concentration time curve values from 0 to infinity (AUC0–∞) were compared after a single and multiple dose(s) of a test or reference drug. The aim was to determine if there were systematic changes in the limits of the single dose confidence interval at steady state that would limit the usefulness of confidence intervals following a single dose in accurately predicting bioavailability following multiple dosing.The 90 per cent confidence interval expressed as a percentage of the reference mean for Tmax, Cmax, and AUC0–∞showed model dependent changes from single to multiple dosing in response to the level of data error and changes in absorption. Changes in clearance also seemed to have a marked effect on the observed limits of the single and multiple dose confidence intervals especially for Cmaxwhich showed a characteristic change in the intervals as a function of the clearance ratio. The model used to describe phenytoin had confidence intervals for Cmaxand AUC0–∞from single to multiple dosing that were similar to that seen for the experimental data. However, the model predictions for Tmaxconfidence intervals following single and multiple dosing was at variance with the experimental data for formula

ISSN:0142-2782    

DOI:10.1002/bdd.2510100507

出版商:John Wiley&Sons, Ltd.    

年代:1989

数据来源: WILEY

摘要:

AbstractSystemic clindamycin absorption was examined in 12 male Caucasians without acne who recieved 1 ml of Cleocin‐T® and 1 ml of 1 per cent clindamycin HCl in Vehicle‐N® (Neutrogena) applied topically the face every 12 h for 4 days according to a crossover design. In a separate phase clindamycin phosphate was administered by an IV infusion of 300 mg over 10 min. Systemic absorption was much higher with clindamycin in Vehicle‐N than with Cleocin‐T. Absolute bioavailability calculated from cumulative urinary excretion and serum AUCs were in good agreement and averaged 1·7 per cent and 7·5 per cent for Cleocin‐T and clindamycin in Vehicle‐N, respectively. Peak serum concentrations ranged from less than 0·5 ng ml−1to 6 ng ml−1for Cleocin‐T and from 4–20 ng ml−1for clindamycin in Vehicle‐N. Absorption profiles indicated zero order absorption with Cleocin‐T. No appreciable systemic accumulation from the repeated topical applications was noted. Systemic exposure to clindamycin from

ISSN:0142-2782    

DOI:10.1002/bdd.2510100508

出版商:John Wiley&Sons, Ltd.    

年代:1989

数据来源: WILEY

摘要:

AbstractEquations were examined to predict or correlate steady‐state (SS) plasma concentrations and single‐dose (SD) data for pharmacokinetic systems with various types of input and nonlinear elimination. The effects of variation of the Michaelis‐Menten parameters, input rate of drug, or bioavailability on the predictability of steady‐state plasma concentrations from single‐dose data were demonstrated by computer simulations for a one‐compartment model. Use of apparently linear equations with Michaelis‐Menten parameters to predict steady‐state plasma concentrations from single dose data is adequate only in limiting low single‐dose cases. Linear SS versus SD correlations for both intravenous and oral dosing can be observed in population data only whenKmis the principal variable; other conditions produce curvilinear behavior. Equations to calculate values of the Michaelis‐Menten parameters from dual single‐dose and steady‐state AUC values are derived and tested for drugs which are intravenously administered. These equations and simulations provide insight into factors determining the relationship between SS and SD AUC for drugs wit

ISSN:0142-2782    

DOI:10.1002/bdd.2510100509

出版商:John Wiley&Sons, Ltd.    

年代:1989

数据来源: WILEY

ISSN:0142-2782    

DOI:10.1002/bdd.2510100510

出版商:John Wiley&Sons, Ltd.    

年代:1989

数据来源: WILEY

ISSN:0142-2782    

DOI:10.1002/bdd.2510100501

出版商:John Wiley&Sons, Ltd.    

年代:1989

数据来源: WILEY