Читать книгу Physiologically Based Pharmacokinetic (PBPK) Modeling and Simulations - Sheila Annie Peters - Страница 40

The exposure of a drug in the body is determined by the rate and extent of absorption, distribution, metabolism, and excretion of the drug in an individual, each of which are impacted by drug properties, physiology as well as the activities of enzymes, transporters, and plasma proteins in that individual. Multiple factors impacting these biological parameters (Table 1.3) include demographics (age, gender, ethnicity, height, and weight), genetic polymorphism, renal or hepatic impairment, obesity, and pregnancy (Figure 1.11). Thus, the pharmacokinetics of a drug is associated with interindividual variability.

Figure 1.10. An orally administered drug or a prodrug may undergo first‐pass metabolism both in the gut and liver resulting in the formation of active metabolite. Both drug and metabolite may be eliminated in each of these organs. For simplicity, the active metabolite formed in the two organs are generally assumed to be completely available in systemic circulation without any elimination in the organ of origin. The fraction of drug bioavailable after first‐pass extraction in systemic circulation is handled similar to IV. Therefore, the amount of metabolite at a given time in systemic circulation is the sum of the amounts of active metabolite from first‐pass and from the biotransformation of the bioavailable fraction of parent drug.

TABLE 1.3. Impact of changes in biological parameters on pharmacokinetic properties.

PK property	Change in biological parameter	Causes	Impact on PK
Absorption	Decrease in small intestinal surface area Reduced gastric emptying rate Increase in gastric pH	Disease or age Fed state; type of food Disease; age; some drugs Fed state	Reduced absorption Slower rate of absorption Reduced solubility of basic drugs
Distribution	Increased body fat relative total body water Reduced albumin Increased AGP	Obesity Liver disease Obesity	Increased volume of distribution of lipophilic drug. Reduces protein binding of acidic drugs and increases that of basic drugs. Appropriate changes to both drug distribution and metabolism.
Metabolism	Reduced CYP activity	Polymorphism Disease or age	Reduced metabolism
Elimination	Reduced GFR and tubular functions	Age	Altered elimination of drugs that are predominantly cleared by the kidney. For compounds that are glucuronidated, the parent drug recirculates for longer due to reduced elimination of the glucuronide.

Figure 1.11. Sources of variability in the physiological parameters that impact pharmacokinetics.