Basic Concepts and Experimental Methods of Pharmacokinetics

Summary The one compartment-body model considers that the drug is homogeneously and rapidly distributed in the total equilibrated volumes of distribution, VF, and that the sum of its rates, R, of removal are proportional to the concentration, b, in those fluids: R = keb. This model requires intravenous administration and extremely rapid equilibration. The apparent elimination rate constant, ke, can be determined from the slope of semilogarithmic plots of the blood concentration against time, In b = -ket + In b0 or of the amount of drug not-yet-excreted, U∞ - U, against time: In (U∞~~ U) = In U∞-ke t . The apparent volume of distribution of the equilibrated fluids, V F is obtainable from the quotient of the dose, D0, and the extrapolated concentration of drug in the blood at zero time, b0, i.e. VF = D0/b0. Alternatively, plots of the instanteous rates of urine excretion, RU, of unchanged drug against the blood concentration, RU = keVfb, permit estimates of renal clearance from the slope, keVf. The slopes of semilogarithmic plots of the renal excretion rate against time also permit estimates of the elimination rate constant, In RU = In keVFb0 -ket. When the drug is eliminated from the body by parallel first order routes of metabolism, renal excretion, etc., the elimination rate constant is the sum of the separate rate constants for renal excretion, ke,U; for metabolism, ke,M; etc. Similar treatments as those explained above for drug blood level, drug amounts in urine, amounts of metabolites formed as a function of time give the ke and VF values. The ratios of the amounts formed as metabolites, M, to the amounts renally excreted, U, at any time are in the ratio of the individual rate constants ke,M/ke,U = M/U. Under usual conditions, when the rate of distribution in the equilibrated body fluids is fast relakT, B, kB,U tive to the elimination rates, the two compartment body model: Tissue Blood Urine, quickly reduces to the one compartment-body model (Tissue + Blood) Urine and the observed elimination rate constant, ke is a function of the intrinsic rate constants: where VB/VF is the fraction of the volumes of distribution that is blood. VB may be obtained from the extrapolated zero time value, b0, of the blood concentration vs. time plot before distribution of the intravenously administered dose, D0 i.e. Thus, from the above expressions and the fact that VF = VB + VT, the volume of tissue, T, may be extracted. For many drugs that are not excessively protein bound, VB is greater than the true plasma volume and includes those fluids from which drug access from the blood is virtually instantaneous. The true pharmacokineticist has already performed preliminary studies on protein binding and partition into red blood cells so that only the free and unbound drug in the plasma water is used in calculating volumes of distribution. The Vp for most drugs is reasonably close in value to the extracellular water of the body and includes all well vascularized tissues. The only way to estimate the distributive constants is by intravenous dosing. The only way to assume that ke values obtained on oral or depot administration are valid estimates is to appreciate by such studies that the distributive processes are fast. The multi-compartmental body model includes “deep” compartments that never equilibrate with the drug in the blood throughout the elimination processes. Such compartments may be bone, fat, eosinophiles, embryos, etc. Their existence allows the body to retain drug for longer periods than the arbitrary half-life estimates made on the basis of a major depletion of drug content in the body would permit. The reliability of a first order multicompartmental model for the distribution, metabolism and excretion of a drug can only be tested by varying intravenous dosage within the clinical dose range and determining whether the derived intrinsic rate constants and apparent volumes of distribution are invariant with dose. The apparent elimination or metabolic rate constant will vary with dose when the blood protein and the enzymic processes are saturable; or when the drug has the property of changing the diffusivity, permeability or size of distributive compartments as a function of dose. Protein binding effects can be analyzed in vitro. Enzymic saturation can be checked with microsomal preparations in vitro or with competitive inhibitors in vivo. Metabolite administration concomitant with drug should permit a decision as to whether the enzymic system is product-inhibited. Biliary excretion rates may be monitored as functions of doses. Independent checks of cardiac volume and renal clearance are helpful to assign the dependence of pharmacokinetic parameters on dose. Occasionally the rate of metabolite appearance does not mirror the loss of drug and may be assigned to storage of metabolite or precursor in an intermediate compartment such as the liver. The phenomenon of enterohepatic circulation may be clarified by monitoring biliary excretion and fecal content simultaneously; or on pharmacokinetic studies with oral administration of the metabolite. The pharmacokinetics of metabolites should be monitored and it must be realized that their volumes of distribution are not those of their drug precursor. The possibilities of enzymic induction in the intact animal should not be ignored. It can be readily checked by determining blood levels and urinary excretion rates at selected times after repetitive daily administration of the drug at intervals that do not implicate cumulative effects. The amounts of drug absorbed and the effects of administrative routes can be evaluated by monitoring the perturbation of the pharmacokinetic parameters obtained previously on intravenous administration. Absorption rates and biological availability of the drug from various forms can be compared on the basis of how much relative material is in the different compartment as a function of time. The perturbations of magnitudes of pharmacokinetic parameters among individuals challenged with a drug can be used as a diagnostic tool in evaluating the state of dynamic processes, the presence of metabolic diseases and genetic abnormalities, and the failure of physiological functions. The correlation of pharmacokinetic parameters with structural modifications of the drug molecule may provide insight into those body distributive and elimination factors which affect the intensity and duration of drug action. The variation of the time-course of drug distribution in a complex organism when considered with the concomitant time-course of pharmacological activity can give insight into the properties and nature of the compartment in contact with the receptor sites, i. e. the biophase compartment.