This review describes the physicochemistry and pharmacokinetic principles of gyrase inhibitors in relation to their distribution in the gastrointestinal tract. Their basicity and lipophilicity at physiologic pH, which affect their disposition in the gastrointestinal tract, are weakened or strengthened by substitutions on the quinoline nucleus. Heterocyclic substitution at position 7 significantly increases basicity and affects lipophilicity considerably. At physiologic pH, the 3-carboxyl group adds significant negative charge. The balance between the negatively charged carboxyl group and the positively charged heterocycle substitutions determines the pH-dependent ratio between ionized and un-ionized species and the solubility and lipophilicity of gyrase inhibitors. After oral administration, both the maximal plasma concentration (Cmax) and time to reach this value (Tmax) are affected primarily by the absorption constant. Absorption of N4'-methylated gyrase inhibitors tend to be greater than that of nonmethylated compounds. Acid-base properties affect absorption as do solubility and dissolution rates. Gyrase inhibitors probably are absorbed primarily in the upper gastrointestinal tract. Food does not alter overall absorption of several gyrase inhibitors studied but prolongs the Tmax slightly but significantly. N4'-methylation appears to protect against effects of food. Delay in gastric emptying may cause the increase in Tmax of gyrase inhibitors ingested with fatty meals. Effects of antacids on absorption of gyrase inhibitors depend on the interval between administration. Other ions also may reduce the absorption of gyrase inhibitors, but histamine-2 (H2)-antagonists appear to affect intestinal absorption of some, but not all, gyrase inhibitors. Gyrase inhibitors undergo significant gastrointestinal elimination.