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mechanism for nonlinear kinetics is saturation in one or multiple

ADME processes as described below:

1. Nonlinear absorption:

• Saturable active GI transport (e.g., riboflavin, levodopa, P-lactam antibiotics)

• Poor aqueous solubility or slow release (e.g., griseoful-vin, phenytoin)

• Saturable presystemic metabolism (e.g., propranolol, telithromycin)

2. Nonlinear distribution:

• Saturable protein binding (e.g., prednisolone/prednisolone)

• Saturable red blood cell binding

• Saturable tissue binding (e.g., paclitaxel)

3. Nonlinear elimination

• Saturable elimination (e.g., phenytoin, theophylline)

• Saturable renal elimination

• Cofactor depletion (e.g., glutathione depletion after acetaminophen overdose)

Dose

Fig. 6.8. Dose Proportionality: Linear vs. Nonlinear

Dose

Fig. 6.8. Dose Proportionality: Linear vs. Nonlinear

• Mechanism-based inhibition (e.g., clarithromycin due to the formation of a stable metabolite-intermediate complex) 4. Autoinduction (e.g., rifampicin, many antiepileptics)

Lack of dose proportionality does not imply a failed compound but it has important implications with regard to safety or efficacy, depending on the mechanism involved, when adjusting dose is needed clinically. For a drug that processes a saturable absorption, efficacy can become a concern. For a drug that shows a saturable elimination, safety is a concern, especially when a drug has a narrow therapeutic window. Nonlinear kinetics usually implies larger inter-subject variability in phar-macokinetics and less predictable drug activity for a given dose across patients or in the same patient at different doses. Ideally, the drugs are easier to manage clinically if their PK are linear at their therapeutic dose range.

Although pharmacokinetic drug-drug interactions (DDI) can occur at any process of ADME, metabolism has been the primary site or mechanism for many clinically important drug interactions (Fig. 6.9). The emphasis of drug-drug interaction studies is on NCEs with a narrow therapeutic index and primarily metabolized via one metabolic pathway and also on potent enzyme inhibitors or inducers. Drug metabolism is primarily mediated by phase I CYP family of isoenzymes (cytochrome P450 enzymes) in the liver, which includes 1A1/2, 2D6, 3A4, 2C8/9/19, and to a small extent, 2B6. The relative amount of the isoforms of the CYP 450 enzymes is listed in this figure [3]. Phase II metabolism is also common by N-acetyl-transferase liver enzymes (NAT 1/2). Genetic polymorphism of these isozymes and DDI are common sources of variability. Drugs may be metabolized by more than one enzyme. For example, tricyclic antidepressants are metabolized by CYP2D6, CYP3A4, and CYP1A2. Also, (S)-warfarin is metabolized by CYP2C9 and (tf)-warfarin metabolized by CYP3A4 and CYP1A2. Genetic absence of one isoenzyme can lead to compensation through the secondary isoenzyme pathway.

r Gastrointestinal absorption c Binding / chelation of drugs o GI emptying / motility r Plasma & tissue protein binding r Drug transporters c Pgp, OCT, OAT, & OATP

r Metabolism

^ Primarily mediated by CYP isozymes: 1A1 / 2, 2D6, 3A4, 2C8/9/19 c Genetic polymorphism CYPs & DDI common sources of variability o Drugs may be metabolized by more than one enzyme o Drug may induce / inhibit 1 isoenzyme but may not be its substrate c Inhibition or induction of an interacting drug may or may not result in clinically significant interaction r Excretion

Fig. 6.9. Sites of Pharmacokinetic Drug Interactions

Source: Li AP. Advances in Pharmacology: Drug-Drug Interactions. Scientific and Regulatory Principles. 1997:43:189. Academic Press, San Diego, CA

r Gastrointestinal absorption c Binding / chelation of drugs o GI emptying / motility r Plasma & tissue protein binding r Drug transporters c Pgp, OCT, OAT, & OATP

CYP 450 Isozyme

Substrates

Inducers

Inhibitors

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