A drug's physicochemical properties fundamentally influence its metabolism. For instance, a drug's molecular size and shape critically determine its interaction with enzymes and transporters — larger drugs may face difficulty reaching enzyme active sites, altering their metabolic pathways. The pK_a of a drug, which establishes its ionization state, can impact its solubility and absorption, thereby influencing metabolism.

The drug's acidity or basicity is essential in determining the metabolic reactions it undergoes. Acidic drugs tend to be metabolized by phase II reactions like glucuronidation, while basic drugs usually undergo phase I reactions such as oxidation or hydroxylation.

Lipophilicity, the drug's propensity to dissolve in lipids, influences its ability to cross cell membranes and interact with liver enzymes, which are key to its metabolism. Steric and electronic characteristics can also affect metabolism; steric hindrance from bulky substituents can impede enzyme access, and electronic features can alter the drug's reactivity with metabolic enzymes.

The stereochemical nature of a drug, particularly the presence of chiral centers, can result in different metabolic pathways and metabolite formation.

Chemical factors also play a pivotal role in drug metabolism. Induction of drug-metabolizing enzymes can increase metabolism rates, potentially reducing drug concentrations and therapeutic effects. Conversely, inhibition of these enzymes can lead to increased drug concentrations, posing potential toxicity risks.

Environmental chemicals can also modulate drug metabolism. Certain pesticides and industrial chemicals may induce drug-metabolizing enzymes, thereby increasing metabolism and reducing drug efficacy. On the other hand, chemicals like those found in grapefruit juice can inhibit these enzymes, leading to increased drug concentrations and potential adverse effects. Understanding these factors is vital for predicting drug efficacy, drug-drug interactions, and potential adverse effects.