The Biophase Compartment

Expressing these in Laplace notation (see Appendix I) gives two simultaneous equations (Equations 19.2 and 19.3)/ 

Substituting X(s) as defined by Equation 19.3 into Equation 19.5 yields 

Taking the inverse Laplace transform of this expression for the general case when koi koB . 

If we make the assumptions that drug distribution to and from the site of action is first order (i.e./ no active transport is involved) and that drug actions are directly determined by the unbound/ unionized drug concentration in water at the site of actioii/ then at steady state the drug concentration in plasma water will be directly proportional to its concentration at the site of action. We can therefore use parameters estimated from biophase concentrations (such as the EC50) to predict the drug effects from unbound/ unionized plasma concentrations. 

A characteristic feature of delayed response is the existence of a hysteresis loop when plasma concentrations are plotted against effects occurring at the 

---

Figure 2.11). The model also includes a compartment for the drug that is reversibly bound to tissues and blood. The significance of this will be explored after further examination of the role of the biophase. 

The effect-compartment model relaxes the assumption H3 and it stems from the assumption of prereceptor nonequilibrium between drug concentration in the blood or plasma c (t) and the receptor site y (t). According to this model, an additional compartment is considered, the effect (or biophase) compartment, and... 

Numerous applications of pharmacokinetic-dynamic models incorporating a biophase (or effect) compartment for a variety of drugs that belong to miscellaneous pharmacological classes, e.g., anesthetic agents [419], opioid analgesics [420-422], barbiturates [423,424], benzodiazepines [425], antiarrhyth-mics [426], have been published. The reader can refer to a handbook [427] or recent reviews [405] for a complete list of the applications of the biophase distribution model. 

FIGURE 20.9 This tolerance model utilizes a hypothetical compartment (Tol) to measure the amount of tolerance in the system. Tol can act as a competitive or noncompetitive antagonist to the effect. The rate of tolerance development and recovery is determined by kjoi and the effect model is direct. A biophase compartment, Q, could have also been added (see Figure 20.10). (Adapted from Refs. 61 and 62.)... 

Instead of being carried to the biophase, the drug can be concentrated in the fat storage compartment. 

The optimal administration of drugs in clinical practice is facilitated by effective application of the principles of clinical pharmacokinetics (PK) and pharmacodynamics (PD). Relationships between drug levels in the systemic circulation and various body compartments (e.g., tissues and biophase) following drug administration depend on factors governing drug absorption, distribution, elimination, and excretion (ADME). Collectively, the study of the factors that govern the ADME processes is termed pharmacokinetics. 

Biophase Distribution Model. Drug distribution to the effect site may represent a rate-limiting step for drugs in exerting their pharmacological effect. Holford and Sheiner introduced a hypothetical effect-compartment (Fig. 7), and proposed that a drug must first enter this effect compartment from either the central or the peripheral pharmacokinetic compartment before its pharmacological response is exerted. ... 

---