Biomedical subjects
Publications and source records attributed to S Keiding.
This review emphasizes the need for well-defined models for hepatic pharmacokinetics and discusses the interpretation of hepatic clearance measurements. Such recent approaches are subjected to theoretical and experimental comparisons. The pharmacokinetic consequences, including a classification of drugs according to hepatic clearance, are outlined.
A new experimental design was developed to study the value of clinical parameters of disease activity in patients with rheumatoid arthritis. Ten patients with classical rheumatoid arthritis were examined by five senior doctors in a department of medical rheumatology. In spite of an attempt to make the clinical examination as uniform as possible the inter-observer variation among the doctors was greater than the variation among the patients, for the following parameters: joint pain at rest, joint tenderness and joint swelling. An acceptable inter-observer variation in relation to patient variation was found for 1) a combined registration of joint pain at rest or on movement, 2) duration of morning stiffness, 3) grip strength, 4) subjective well-being as indicated on a visual analogue scale, 5) fingertip--palm distance, and 6) maximum flexion-extension in elbows, wrists and knees. The variation from morning to afternoon and from day to day was negligible. It is concluded that registration of elaborated articular scores is useless in the daily routine in rheumatological departments when different doctors examine the patients.
Three hepatic clearance regimes (flow-limited, general, and enzyme-limited) can be defined from a model of hepatic perfusion-elimination relationships. Substances that can be used for clearance measurements can thus be classified into three categories according to the relation between their kinetic elimination constants (Vmax, Km) and hepatic blood flow. The pathophysiologic and clinical importance of the clearance regimes is discussed with special emphasis on the effect of changes in hepatic blood flow and liver function. The criteria for choosing test substances within each regime are stated. This choice depends on the object of study for a clearance measurement (blood flow, drug elimination, liver function). Only the enzyme-limited clearance regime is suited for direct assessment of quantitative liver function ('true clearance'), while the other regimes depend more or less on blood flow.
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The purpose of the present study was to define the elimination kinetics of phenazone (NFN) in the isolated perfused pig liver. In five experiments phenazone was administered as constant infusion to obtain steady-state periods over a wide range of concentrations. The elimination of phenazone followed saturation kinetics (concentrations 0.1-12 mmol x 1(-1) and the maximal elimination rate (Vmax) was on average 102 mumol x min-1 x kg-1 liver and the Michaëlis-constant (Km) of 2.6 mmol x 1(-1). Estimates of Vmax and Km for the microsomal phenazone hydroxylase activity measured in liver biopsies found to be considerably lower than in the perfused liver. The hepatic elimination of phenazone during perfusion of pig liver at phenazone concentrations corresponding to human therapeutic doses follows first-order kinetics.
The effect of ethanol (5--25 mM) on the galactose elimination kinetics in the intact liver was studied in the isolated perfused pig liver, using the steady-state infusion technique. Ethanol reduced galactose-Vmax on average to 0.07 mmol/min kg liver in six experiments from 0.43 mmol/min kg obtained in control experiments without ethanol. Also Km was significantly reduced from 0.23 mmol/l plasma water to 0.03 mmol/l. Ethanol increased UDP-galactose ten-fold simultaneous with a rise in hepatic outflow ratio of lactate to pyruvate to about 300 from 10; this indicates that ethanol inhibits epimerase. In experiments with increasing galactose elimination rates, the concentration of galactose-1-P increased much less than the concentration of galactose, and the phosphorylation of galactose therefore seems to be rate-limiting. In vitro galactokinase is inhibited by galactose-1-P. In the present study ethanol increased galactose-1-P five to ten times, and the reduction of Vmax and Km by ethanol could be explained by uncompetitive inhibition by galactose-1-P with Ki about 0.1 mmol/l. Ethanol decreased UDP-glucose to about 40% and UTP to less than 5%, probably due to trapping as UDP-galactose. This may depress the forward transferase reaction, and therefore the other co-substrate galactose-1-P rises--and inhibits galactokinase.
1. The galactose-elimination rate in perfused livers from starved rats was decreased in the presence of ethanol (2-28mM) to one-third of the control values. Orotate injections partly reversed the effect of ethanol, so that the galactose-elimination rate was about two-thirds of the control values. Orotate alone had no effect on the galactose-elimination rate. 2. Ethanol increased [galactose 1-phosphate] and [UDP-galactose], and decreased (UDP-glucose] and [UTP], both with and without orotate. Orotate increased [UTP], [UDP-galactose], both with and without ethanol. The increase of [galactose 1-phosphate] in the presence of ethanol was inhibited by orotate. Orotate alone had no appreciable effect on [galactose 1-phosphate]. 3. Both the effect of ethanol and that of orotate on the galactose-elimination rate can be accounted for by assuming inhibition of galactokinase by galactose 1-phosphate with Ki about 0.2mM, the inhibition being either non-competitive or uncompetitive. 4. The primary effect of ethanol seems to be inhibition of UDP-glucose epimerase (EC 5.1.3.2), followed by accumulation of UDP-galactose, trapping of UDP-glucose and increase of [galactose 1-phosphate]. Orotate decreased the effect of ethanol, probably by increasing [UDP-glucose].
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The galactose elimination capacity (GEC) of rats fed low protein liquid diets and libitum with 5% or 0.5% of the energy as protein was compared with that of a control group receiving a similar diet with 25% of the energy as protein. The daily dietary energy intake was almost identical in the three groups. The rats fed the 5% protein diet showed slightly higher GEC than the control group. In the rats receiving the 0.5% protein diet, GEC was significantly decreased to approximately half of the control values and the hepatic protein content was reduced to the same extent. Body weight and liver weight showed reductions to approximately 75% of control values. Triglyceride content in the livers was increased five times in the protein depleted rats. The results indicate that GEC in rats deprived of dietary protein is determined by the amount of hepatic protein.
The relation between galactose elimination rates and blood concentrations in the isolated perfused pig liver was analyzed by a mathematical kinetic model. It assumes that the substrate, under steady-state conditions, is removed from the blood that flows through the sinusoids by an irreversible process which follows Michaelis-Menten (i.e., saturation) kinetics. The experiments consisted of successive periods with constant infusions of galactose. The model fitted the data to within the experimental uncertainty. The estimated maximal rate (Vmax) ranged from 0.34 to 0.57 mmol-min(-1)-kg(-1) liver, and the Michaelis constant, Km, ranged from 0.12 to 0.30 mmol-liter(-1) plasma water in nine experiments. The ratio between the galactose concentration in hepatocyte water and plasma water was not significantly different from 1.0, indicating that membrane transport is not rate limiting for the elimination of galactose. In experiments with increasing concentrations of galactose in hepatocyte water and approximately saturated elimination rates, the concentrations of galactose 1-phosphate, UDPgalactose, and UDPglucose remained essentially constant. This indicates that the phosphorylation of galactose to galactose 1-phosphate is the rate-determining process.
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