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Biomedical subjects

M Rowland

Publications and source records attributed to M Rowland.

At least 199 records · Page 11Linked to original sources
PubMed1984

Representation and quantitation of the binding interaction between prednisone, prednisolone and corticosteroid binding globulin.

The interaction between prednisone and prednisolone (0-500 ng ml-1) for binding sites on corticosteroid binding globulin (CBG) in rabbit plasma has been investigated. The fraction unbound of each steroid rose markedly with increasing concentration at low concentrations (250 ng ml-1), tending to a plateau (0.29 prednisone, 0.15 prednisolone) at the higher concentrations (250-500 ng ml-1), indicating both saturation of CBG and the importance of binding to albumin in higher concentrations. A method is proposed of representing graphically the prednisone-prednisolone-protein interaction in three dimensions.

Animals↗
PubMed1984

Protein binding and drug clearance.

Most drugs are given continuously. Clearance, the parameter which relates rate of elimination to drug concentration, is important because it defines the rate of administration required to maintain a plateau drug concentration. Together with the extent of distribution outside of plasma, clearance also determines the speed at which a drug is eliminated from the body. The sensitivity of organ clearance of a drug to changes in binding within blood depends on its unbound clearance. If unbound clearance is low, relative to organ blood flow, the extraction ratio (and clearance) will always be low and dependent on plasma binding. If the extraction ratio is high, elimination becomes perfusion rate-limited and clearance will be relatively insensitive to changes in binding, but oral bioavailability may exhibit dependence on binding if the liver is the major eliminating organ. A full insight into the implications of altered binding on pharmacokinetics requires a sound understanding of the physiology both of the eliminating organs and the distribution of drug within the body. Such information is steadily being acquired.

Animals↗
PubMed1984

Influence of route of hepatic administration on drug availability.

The work investigates functional variability of hepatic arterial and portal venous streams in relation to drug availability. In an isolated rat liver system perfused in all experiments at a constant total flow of 10 ml X min-1, drug availability was found to be 18 and 3 times greater for lidocaine and meperidine, respectively, when infused through the hepatic artery compared to portal vein administration. When both hepatic artery and portal vein were perfused, drug availability increased log linearly for lidocaine, and linearly for meperidine with increasing hepatic artery flow contribution. Injection of 15-micron gamma-labeled microspheres into the hepatic artery and portal vein did not reveal arteriovenous or portovenous shunting channels greater than 15 micron in diameter. However, the ratios of the mean transit times of albumin and red blood cells were found to be significantly lower through the hepatic artery, indicating a possible reduction in perisinusoidal albumin space. When both hepatic artery and portal vein were perfused, linear correlations were obtained for values of this ratio plotted against increasing hepatic artery flow contributions. Data from the red blood cell transit time studies, as well as data on lidocaine availability, suggest the presence of functionally separate capillary beds for the hepatic arterial and venous streams.

Albumins↗
PubMed1984

Relationship between renal clearance, protein binding and urine flow for digitoxin, a compound of low clearance in the isolated perfused rat kidney.

An isolated perfused rat kidney preparation is described which allows the relationship between protein binding and renal clearance to be studied in a quantitative manner. The influence of unbound fraction of drug in the perfusate, urine pH and urine flow upon the renal clearance of digitoxin is examined. Renal clearance and unbound fraction were found to be related linearly. Urine pH did not influence digitoxin renal clearance but urine flow did, in a nonlinear manner. A simple physiologically based model of renal clearance is developed which predicts the influence of urine flow and protein binding upon digitoxin clearance in this preparation.

Animals↗
PubMed1983

Prevalence of myopia in the United States.

Data from the 1971 to 1972 National Health and Nutrition Examination Survey were used to estimate myopia prevalence rates for persons in the United States between the ages of 12 and 54 years. When persons were classified by the refractive status of their right eye, 25% were myopic. Significantly lower prevalence rates were found for male subjects than for female subjects and for blacks than for whites. Myopia prevalence rose with family income and educational level. The importance of income and educational level may result from their association with near work, a factor that has been implicated in the pathogenesis of myopia.

Adolescent↗
PubMed1983

Stereospecific high-performance liquid chromatographic analysis of warfarin in plasma.

A stereospecific high-performance liquid chromatographic assay has been developed to determine R(+)- and S(-)-warfarin simultaneously in plasma. The method involved the formation of diastereoisomeric esters, using carbobenzyloxy-L-proline, with subsequent separation using silica as the stationary phase. The method permits characterization of the pharmacokinetics of warfarin enantiomers following administration of racemic drug.

Chromatography, High Pressure Liquid↗
PubMed1983

Protein binding and hepatic clearance: studies with tolbutamide, a drug of low intrinsic clearance, in the isolated perfused rat liver preparation.

The influence of altered drug binding on the hepatic elimination of tolbutamide, a drug of low intrinsic clearance, and on the formation of its metabolite, hydroxytolbutamide, was examined under linear conditions at steady state in the isolated in situ single-pass perfused rat liver preparation, with perfusate flow fixed at 15 ml/min. The fraction of tulbutamide unbound in the perfusate was varied (from 0.06 to 1.0) by either varying the perfusate concentration of albumin or using albumin of different animal species. The intrinsic clearance of tolbutamide varied fourfold between preparations (0.08-0.36 ml/min/g liver). Within each preparation the data were normalized to observations with a perfusate containing no protein. Both the extraction ratio (and clearance) of tolbutamide and the fraction of tulbutamide appearing as hydroxytolbutamide in effluent perfusate, a measure of hepatic metabolism, were directly proportional to the fraction of tolbutamide unbound in the perfusate.

Animals↗
PubMed1983

Phenylbutazone-warfarin interaction in man: further stereochemical and metabolic considerations.

The pharmacokinetics and urinary metabolic profile of R and S-warfarin, following administration of a 1.5 mg/kg oral dose of racemic warfarin, alone and 4 days into an oral regimen of 100 mg phenylbutazone three times a day, was investigated in three volunteers using a stereospecific h.p.l.c. fluorescent assay. The mean elimination half-life of S-warfarin was increased from 25 to 46 h during phenylbutazone administration, whilst that of the R-isomer was decreased from 37 to 25 h. The peak unbound concentrations of both warfarin enantiomers were higher during phenylbutazone administration, due to displacement. Displacement was not stereoselective. The unbound clearance of more potent S-warfarin is decreased by four-fold during phenylbutazone administration, due to substantial inhibition of both 6- and 7-hydroxylation, significant pathways of elimination of S-warfarin in the absence of phenylbutazone. The unbound clearance of R-warfarin is almost unchanged during phenylbutazone administration, due to the marginal effect of phenylbutazone on 6- and 7-hydroxylation, themselves minor pathways of elimination of this enantiomer in the absence of phenylbutazone. The stereoselective reduction of S- and R-warfarin, to their respective SS and RS-alcohols, is also substantially inhibited during phenylbutazone administration. Collectively the data point to the complex effect of phenylbutazone administration on warfarin's pharmacokinetics.

Drug Interactions↗
PubMed1983

Cyclic interconversion of vitamin K1 and vitamin K1 2,3-epoxide in man.

The disposition of a single intravenous bolus dose of 10 mg vitamin K1 and vitamin K1-2,3-epoxide were studied in two healthy subjects without and with 12 h pretreatment dose of phenprocoumon (0.4 mg/kg). For each compound administered alone the plasma concentration-time profile was adequately fitted by a biexponential equation, with an average terminal half-life of 2.0 and 1.15 h for the administered vitamin K and its 2,3-epoxide respectively. While vitamin K1 was measurable in plasma following administration of vitamin K1-2,3-epoxide, the epoxide was not detectable following administration of vitamin K1. Following pretreatment with phenprocoumon and after intravenous administration of vitamin K1, both the average half-life and area under the plasma concentration-time profile of vitamin K1 were marginally reduced to 1.5 h and 1.76 mg l-1 h respectively, while the plasma concentration of vitamin K1-2,3-epoxide was readily measurable and its half-life markedly prolonged to 14.7 h. Following pretreatment with phenprocoumon and after oral administration of vitamin K1-2,3-epoxide, no vitamin K1 was detectable in plasma and the half-life of the epoxide was 13.8 h. Based on area considerations the data suggest that either phenprocoumon does more than just inhibit the reduction of vitamin K1-2,3-epoxide to vitamin K1, or that the simple model describing the interconversion between vitamin K1 and its epoxide is inadequate. The same conclusion is drawn from the analysis of comparable data in dogs, obtained by Carlisle & Blaschke (1981).

Adult↗
PubMed1983

Models of hepatic drug clearance: discrimination between the 'well stirred' and 'parallel-tube' models.

The predictive ability of two models of hepatic drug clearance are compared. The 'parallel-tube' model predicts that the steady-state drug concentration following constant rate oral administration increases with increase in hepatic blood flow. The 'well-stirred' model predicts that this parameter is not sensitive to changes in hepatic blood flow. Using the steady-state reservoir drug concentration as the discriminatory index, the predictions of the models were tested in a recirculating isolated perfused rat liver system with lignocaine and pethidine, both of which are highly extracted, as test drugs. The steady-state reservoir concentration of both drugs was found to be constant when flow through the liver was increased from 10 ml min-1 to 15 ml min-1. The experimental findings indicate that the 'well-stirred' model more accurately describes the elimination of highly cleared drugs with perturbations of flow than does the 'parallel-tube' model.

Animals↗
PubMed1983

Absorption of prednisolone in patients with Crohn's disease.

The absorption of prednisolone in patients with Crohn's disease was investigated. Seven patients with Crohn's disease and eight normal control subjects were given a tracer dose of tritiated prednisolone with 20 mg cold prednisolone by mouth. On a separate occasion they were given an intravenous injection of radiolabelled prednisolone. After oral ingestion only 53.4 +/- 11.7% of labelled material was excreted in the urine of Crohn's patients compared with 82.5 +/- 3.6% in the normal subjects. The oral/intravenous availability ratio was 0.61 +/- 0.14 in Crohn's patients and 0.89 +/- 0.07 in the normal group. Areas under plasma concentration-time curves were lower in patients than normal subjects and the oral/intravenous ratios were 0.6 +/- 0.2 and 0.86 +/- 0.09 respectively. Faecal excretion of radioactivity after oral ingestion was greater in Crohn's patients (19.3 +/- 2.5%, n = 3) than in normal subjects (7 +/- 2.8%, n = 4). The range for each type of measurement was much wider in the patient group than in the normal subjects. These data suggest that patients with Crohn's disease do not absorb prednisolone normally and that absorption varies between patients.

Administration, Oral↗
PubMed1983

Structure-pharmacokinetic relationships among the barbiturates in the rat.

The pharmacokinetics of a congeneric series of barbituric acids were determined after i.v. administration of individual barbiturates or multicomponent barbiturate mixtures to chronically cannulated male rats. The concentration of barbiturate in plasma and urine was determined using reversed-phase high-performance liquid chromatography. A biexponential equation adequately fitted the plasma-concentration time data. The volume of distribution remained relatively constant within the series. Binding to plasma proteins varied enormously, increasing with lipophilicity. Accordingly, the volume of distribution based on unbound drug also increased with lipophilicity, reflecting a corresponding greater tissue affinity. Total clearance formed a relatively complex nonlinear relationship with lipophilicity. Although the affinity of the barbiturates for erythrocytes increased with lipophilicity, the relationship between total blood clearance and lipophilicity offered no simplification. Renal clearance, the minor route of elimination for the majority of the homologs, decreased with increasing lipophilicity, due to increased tubular reabsorption, whereas nonrenal (hepatic) clearance produced a nonlinear relationship with lipophilicity similar in form to that of total clearance. The nonlinearity of the hepatic clearance within the series was explained by a hepatic blood flow limitation, for the highest homologs, and by the stereochemistry of position 5 on the barbituric acid ring, for the lowest homologs.

Animals↗
PubMed1982

Pharmacokinetics of lidocaine and its deethylated metabolite: dose and time dependency studies in man.

The concentrations of lidocaine and of its deethylated metabolite, MEGX, were measured in blood following the intravenous administration of 50 and 100 mg lidocaine hydrochloride, the oral administration of 100, 300, and 500 mg lidocaine hydrochloride monohydrate, and the oral administration of 300 mg lidocaine hydrochloride monohydrate every 8 h for seven doses, to three healthy volunteers. The range of values for the parameters defining the disposition kinetics of lidocaine were: terminal half-life, 50-231 min; total clearance, 13-17 ml/min/kg; initial dilution space, 0.13-2.5 liters/kg; and volume of distribution at steady state, 0.6-4.5 liters/kg. Lidocaine absorption from solution was rapid, but due to presystemic hepatic metabolism, the availability was low, the range of average values lying between 0.19 and 0.38. No dose or time dependency in lidocaine and monoethylglycinexylidide pharmacokinetics following the single dose studies of lidocaine were noted. Effective hepatic blood flow, based on total clearance and availability measurements, was estimated to be 18-27 ml/min/kg. The concentrations of MEGX were approximately one-third of those of lidocaine following intravenous lidocaine and were comparable following oral lidocaine, but as predicted, the dose normalized area under the MEGX concentration-time curve was constant and independent of the route of administration of lidocaine. In two subjects, the blood concentrations of lidocaine and MEGX following multiple doses of oral lidocaine were those predicted from the single dose studies. In the third subject, the degree of accumulation of lidocaine was greater than predicted. The reasons and mechanism for this difference between subjects on multiple dosing remains unclear.

Administration, Oral↗