Thomas N. Tozer

First-pass elimination: basic concepts and clinical consequences

SummaryFirst-pass elimination takes place when a drug is metabolised between its site of administration and the site of sampling for measurement of drug concentration. Clinically, first-pass metabolism is important when the fraction of the dose administered that escapes metabolism is small and variable. The liver is usually assumed to be the major site of first-pass metabolism of a drug administered orally, but other potential sites are the gastrointestinal tract, blood, vascular endothelium, lungs, and the arm from which venous samples are taken. Bioavailability, defined as the ratio of the areas under the blood concentration-time curves, after extra- and intravascular drug administration (corrected for dosage if necessary), is often used as a measure of the extent of first-pass metabolism. When several sites of first-pass metabolism are in series, the bioavailability is the product of the fractions of drug entering the tissue that escape loss at each site.The extent of first-pass metabolism in the liver and intestinal wall depends on a number of physiological factors. The major factors are enzyme activity, plasma protein and blood cell binding, and gastrointestinal motility. Models that describe the dependence of bioavailability on changes in these physiological variables have been developed for drugs subject to first-pass metabolism only in the liver. Two that have been applied widely are the ‘well-stirred’ and ‘parallel tube’ models. Discrimination between the 2 models may be performed under linear conditions in which all pharmacokinetic parameters are independent of concentration and time. The predictions of the models are similar when bioavailability is large but differ dramatically when bioavailability is small. The ‘parallel tube’ model always predicts a much greater change in bioavailability than the ‘well-stirred’ model for a given change in drug-metabolising enzyme activity, blood flow, or fraction of drug unbound.Many clinically important drugs undergo considerable first-pass metabolism after an oral dose. Drugs in this category include alprenolol, amitriptyline, dihydroergotamine, 5-fluorouracil, hydralazine, isoprenaline (isoproterenol), lignocaine (lidocaine), lorcainide, pethidine (meperidine), mercaptopurine, metoprolol, morphine, neostigmine, nifedipine, pentazocine and propranolol. One major therapeutic implication of extensive first-pass metabolism is that much larger oral doses than intravenous doses are required to achieve equivalent plasma concentrations. For some drugs, extensive first-pass metabolism precludes their use as oral agents (e.g. lignocaine, naloxone and glyceryl trinitrate). Inhalation or buccal, rectal or transdermal administration may, in part, obviate the problems of extensive first-pass metabolism of an oral dose.Drugs that undergo extensive first-pass metabolism may produce different plasma metabolite concentration-time profiles after oral and parenteral administration. After an oral dose, the concentration of the metabolite may reach a peak earlier than after a parenteral dose. Sometimes, metabolites have only been detected in plasma after an oral dose. Drugs in this category include alprenolol, amitriptyline, lorcainide, pethidine, nifedipine and propranolol. Although the plasma concentration-time profiles of metabolites may differ after oral and parenteral doses, the fraction of a dose eventually converted to a metabolite should be the same after each route of administration provided that the ingested drug is completely absorbed, is eliminated solely by metabolism in the liver, and has linear kinetics. Otherwise, the fraction of a dose administered that is converted to a metabolite may vary with route of administration (e.g. with isoprenaline and salbutamol). Variation in the concentration ratios between parent drug and metabolite may produce route-dependent differences in pharmacological and toxicological responses to a given concentration of the parent drug (e.g. with encainide, lorcainide, quinidine and verapamil).Drugs that undergo extensive first-pass elimination exhibit pronounced interindividual variation in plasma concentrations or drug concentration-time curves after oral administration. This variation, often reflected in variability in drug response, poses one of the major problems in the clinical use of these drugs. Variability in first-pass metabolism is accounted for by differences in metabolising enzyme activity produced either by enzyme induction, inhibition, or by genetic polymorphism. Liver disease affects bioavailability by changing metabolising enzyme activity and plasma protein binding, and creating intra- and extrahepatic portacaval shunts. In addition, food, by causing transient increases in splanchnic-hepatic blood flow, may also decrease the first-pass metabolism of certain drugs.The bioavailability of some drugs is dose- and time-dependent. The bioavailability of a single oral dose of 5-fluorouracil, hydralazine, lorcainide, phenacetin (acetophenetidin), propranolol and salicylamide increases as dose increases. When lorcainide, metoprolol, propranolol, dextropropoxyphene (propoxyphene) and verapamil are given repeatedly, their bioavailability increases. This time dependency may not be observed when the drugs are administered intravenously.The liver has been most extensively studied with respect to first-pass metabolism. Relatively little information is available in humans on intestinal or pulmonary metabolism or on the effects of altered organ blood flow and plasma protein binding on first-pass metabolism. These potentially important areas require further exploration to broaden our understanding of the clinically important phenomenon of first-pass metabolism.

The clinical pharmacokinetics of phenytoin

Procedures for estimating the variability in dosage requirements of phenytoin to achieve steadystate plasma concentrations of 10–20 mg/liter and for estimating the plasma concentrations produced on a fixed dose are given. Further, a method is proposed for estimating the dosage required to achieve a desired steady-state plasma phenytoin concentration when a steady-state value on a known daily dose has been measured, A method is also described for estimating dosage requirements when two or more plasma concentrations have been measured. These methods are derived from data obtained on administering phenytoin in four to five different dosage regimens until steady state was achieved in each of nine volunteers. The drug was administered orally as a suspension every 8 hr, starting with about 100mg/day. The daily dose was increased in steps, and maintained at each daily dose rate for 6–14 days, or longer. Blood samples were drawn 4 and 8 hr after the last dose on 2 successive days at the end of each step and analyzed for phenytoin concentration. The average of these values was used to estimate the steady-state plasma concentration, Cpss. For each subject the Cpss values were fitted to a rearranged Michaelis-Menten equation Cpss =KmR/(Vm-R). In this equation R is the dosing rate, Vm is the maximum rate of metabolism, and Km is a constant equal to the plasma concentration at which the metabolism rate is one-half maximum. The average values found for Vm and Km were 10.3 mg/kg/day and 11.54 mg/liter, respectively. The individual values of Vm and Km appear to be constant over time, but there is considerable interindividual variability: coefficients of variation are 25% and 50%, respectively.

Nomogram for modification of dosage regimens in patients with chronic renal function impairment

A nomogram is presented for modifying dosage regimens of drugs administered to patients with chronic renal function impairment. The usefulness and limitations of the nomogram are discussed in terms of the objectives of dosage regimens. The nomogram is intended to serve as a guide for drug administration in patients with renal disease. It may be particularly helpful for drugs on which little or no definitive research has been undertaken.

Pharmacokinetic Evaluation of Hemodialysis in Acute Drug Overdose

The contribution of hemodialysis to the removal of drugs in the overdosed patient continues to be questioned. Often the value of hemodialysis is judged on qualitative rather than quantitative information. The latter information can be obtained by applying pharmacokinetic principles. The primary pharmacokinetic parameters required to evaluate drug removal by hemodialysis are (1) apparent volume of distribution, (2) dialysis clearance, and (3) total body clearance. Eighteen drugs commonly encountered in the overdose setting are evaluated using this approach.

Urine flow-dependence of theophylline renal clearance in man

Theophylline renal clearance is highly dependent on urine flow rate and is neither concentration nor dose related. To examine the flow dependency, theophylline was adminstered in single doses (4.3 mg/kg to 8.6 mg/kg) to 14 volunteers. Seven of these volunteers participated in studies in which theophylline and metabolite concentrations were held constant at six different levels. Due to the diuretic effect of theophylline, its renal clearance contributed up to 70% of the time-averaged total clearance, dose/total area, in the first hour after a single dose. The contribution then dropped to 5% of the time-averaged total clearance when the normal urine flow rate was restored. As a consequence of extensive tubular reabsorption, the urine/plasma concentration ratio of theophylline varied with urine flow rate and approached the value of the unbound fraction in plasma. On assumption that the reabsorption is passive, a mathematical model was used to explain the urine flow dependence of reabsorption and, therefore, the renal clearance of theophylline.

Influence of renal failure on the hepatic clearance of bufuralol in man

The beta-blocking agent bufuralol is subject to first-pass metabolism and is eliminated from the body almost entirely by biotransformation. Its major metabolite in plasma (1′-hydroxy-bufuralol) is biologically active and may contribute to the pharmacological effect of the drug. The effect of renal failure on the behavior of the parent compound and three of its metabolites was studied by comparing their kinetics in normal volunteers and in patients with severe renal insufficiency. Bufuralol was given orally to all subjects (20 mg); some of the healthy volunteers also received the drug intravenously (5 mg). Renal failure was found to be associated with a marked increase of the areas under the plasma concentration-time curves of the parent compound, whereas its halflife of elimination was not markedly influenced. The behavior of 1′-hydroxy-bufuralol was consistent with a decreased renal clearance. The behavior of bufuralol in patients with renal failure was analyzed using the clearance approach. From this analysis it appears that the presystemic biotransformation of bufuralol is decreased in renal failure and that changes in systemic clearance are compensated in our patients by modifications of the volume of distribution, resulting in little net change in the halflife of elimination.

Saturable rate of cefatrizine absorption after oral administration to humans.

This study examined the absorption kinetics of cefatrizine, an amino-β-lactam antibiotic, after oral administration of a single 500-mg dose to 12 healthy volunteers. Plasma concentrations were determined by high performance liquid chromatography. The plots of the percentage of drug unabsorbed and the apparent rate of cefatrizine absorption as a function of time showed, first, a delay and, then, an almost constant rate of absorption with a tendency to move toward first-order kinetics at the end of the process. Three compartmental models incorporating a lag time and first-order elimination kinetics, but differing in their input rate, were used for analysis of the time course of cefatrizine plasma concentrations. The model with first-order absorption kinetics was clearly inadequate. The results were improved with the model for which the rate of absorption is constant, but a model incorporating saturable absorption kinetics of the Michaelis-Menten type improved the fit further. This last model was statistically superior to the constant-rate input model in 6 out of 12 subjects, according to the likelihood-ratio method. Because of the innovative feature of the model incorporating the Michaelis-Menten equation, simulations of the effect of altering the model parameters and the dose administered on the concentration-time profile, were performed. Different hypotheses which might explain why cefatrizine absorption kinetics fits the Michaelis-Menten equation were examined. The observation of saturable absorption kinetics is consistent with a carrier-mediated transport previously reported to occur in the gastrointestinal tract of rats.

Theoretical considerations in the calculation of bioavailability of drugs exhibiting Michaelis-Menten elimination kinetics

Two approaches used for bioavailability determination of drugs with Michaelis-Menten elimination kinetics were examined by computer simulation. The first method involved treating the drug as though its clearance remained constant during elimination, and the conventional method of taking the ratio of areas under the curve resulting from the oral and intravenous doses was used to calculate bioavailability. The second approach involved using the Michaelis parameters, Vmaxand Km,to determine concentration dependent clearance values, but based these calculations on peripheral drug concentrations rather than on concentrations entering or in the liver. We have developed a simulation method that was used to test the accuracy of the above two methods. In the simulations described, Vmax, Km,and hepatic blood flow were chosen to represent a drug with an extraction ratio of 0.9 under linear conditions, but with Michaelis-Menten kinetics occurring at the doses given. Absorption was assumed to be first-order, and metabolism was assumed to occur only in the liver. These simulations showed that the most accurate determination of bioavailability requires knowledge of the direct contribution of oral absorption to the concentration of drug entering the liver. Unexpectedly, the results also showed that if a drug has a large volume of distribution or a large absorption rate constant, or both, use of the much simpler conventional method of bioavailability determination may be appropriate even in cases where the degree of saturation is substantial.

Concurrent intravenous administration of a labeled tracer to determine the oral bioavailability of a drug exhibiting Michaelis-Menten metabolism

The theoretical accuracy of concurrent administration of labeled intravenous tracer and oral doses to estimate the bioavailability of drugs exhibiting Michaelis-Menten kinetics was determined by computer simulation. The simulation model consisted of sampling and hepatic compartments with elimination occurring by hepatic metabolism according to the venous equilibration model. The relationships between error in bioavailability estimation and dose, metabolic activity (Vmax),first-order absorption rate constant (ka), and volume of distribution (V) and the fraction of the dose absorbed were examined. Error was hypothesized to be relatively low when conditions result in a relatively constant value of clearance after oral dosing or when the concentration-time curves after intravenous and oral dosing are similar. The results were consistent with these hypotheses and, under most conditions, error was less than 15%. The effects, on error, of altering the intravenous tracer dose input and having a lag time in absorption of drug from the oral dose were also determined. In general, accuracy was improved by delaying administration of the iv tracer for a time equal to 50% of the oral dose peak time or by administering the tracer dose by constant-rate infusion from the time of oral dosing to the peak time. Lag time in absorption of the oral dose was shown to often result in overestimates in bioavailability of greater than 50%.

Theoretical model for both saturable rate and extent of absorption: Simulations of cefatrizine data

A pharmacokinetic model incorporating saturable rate of absorption of the Michaelis-Menten type was recently developed to fit cefatrizine (CFZ) plasma concentrations with time following oral administration of 500-mg capsules to humans. This model (MM) was statistically superior to models incorporating either first-order or zero-order absorption. However, the MM model does not predict the reduction in extent of absorption with dose observedin vivo. In this study, a model is proposed in which a time constraint, Δt, is added to the MM model. This new model (MM-Δt) is tested with data following doses of 250, 500, and 1000 mg of CFZ. When Δt is set to 1.5 hr, the predicted relative changes with dose in bioavailability,F, peak plasma concentration,Cmax, the time at which the peak concentration occurs,tmax, and the mean absorption time,MAT, are generally in good agreement with the experimental data. The time interval of 1.5 hr is compatible with passage by a limited region within the small intestine where drug is absorbed by a facilitated transport mechanism. Influence of each absorption model parameter (Vmax,Km, and Δt) on total area under the concentration versus time curve (AUC),F,Cmax, andtmax, is assessed by simulation. The MM-Δt model is able to summarize the nonlinearity observed in both rate and extent of absorption.