• Even if a drug is absorbed completely, the plasma concentration can vary depending upon rate of absorption
• extent of absorption indicates area under the plasma conc. vs. time curve – measured by Fo (fraction absorbed orally)
• rate of absorption is unrelated to Fo – if absorption is slow, concentration will be lower but will persist for a longer time
• Example – pentobarbitol is a weak organic acid with pK_a of 7.6; Fo(fed) = Fo(fasting) Þ area under curve is same, but only fasting dose is effective since serum concentration reaches a higher peak resulting from Ý rate of abs. during fast
• antacids, HCO₃^-, and some drugs (e.g., anticholinergics) have the same effect as the fed state (ß rate of abs.)

• Prior to absorption, the drug must be made soluble; this takes place by means of dissolution and disintegration
• determined by surface area of the drug and drug vehicle – solutions and capsules are better than tablets
• determined by volume – absorption of salicylic acid faster if pill is taken with more water (more effective dissolution)
• Dissolution can affect fraction absorbed orally (Fo) as well
• Digoxin is a diuretic that is difficult to dissolve, but which is rapidly absorbed once dissolved
• tablet form has widely variable Fo worldwide due to different preparations (tightly controlled in U.S.)
• capsules Fo =1.0, tablets Fo=0.8 – thus tablets need more drug (0.25 instead of 0.2 mg, 0.125 instead of 0.1 mg)
• Penytoin is used for epilepsy; variations in preparation can lead to ineffectively low/toxically high plasma concentration
• alterations in drug preparation led to epidemics in Australia and Lapland
• binder was changed, which decreased bioavailability

Fick’s Law – Primary Determinant of Absorption of Solubilized Drug

• Diffusion Coefficient – rate of diffusion of individual molecules – relatively constant
• Partition Coefficient (dominant feature!) – fraction of drug that distributes to lipid (vs. aqueous solution) Þ oil ¸ water
• ionized molecules will not partition to the lipid layer (coefficient = 0) – best absorption when uncharged
• salicylic acid (pKa = 3.0) is uncharged only at low pH – raising pH 1 Þ 8 reduces absorption fivefold
• thiopental (pKa = 7.6) is uncharged below neutral pH – raising pH 1 Þ 8 reduces absorption somewhat
• quinine (pKa = 8.4) and dextromethorphan (pKa = 9.2) are uncharged only at high pH – not absorbed at pH 1
• for uncharged molecules, the partition coefficient is the most significant determinant of absorption rate
• drugs with comparable pKa can have radically different rates due to their partition coefficient
• absorption in one hour: 46% of thiopental (PC = 63), 30% of secobarbital (PC = 30), only 4% barbital (PC=.26)
• non-lipid-soluble drugs (e.g., aminoglycosides) are not absorbed–act only inside GI tract when taken by mouth
• Membrane Thickness – usually not a factor – some rare diseases involve thickening of the gut (e.g., celiac disease)
• Surface Area – gut has much more surface area than stomach
• salicylic acid absorption is faster in the gut (100% in 20 minutes) than the stomach (50% in 80 minutes)
• gut pH = 6, which is 3 units above pKa – so, although 99.9% is ionized in the gut, absorption is still more efficient
• therefore surface area is critical - Ý SA Þ Ý absorption, even if pH is not low; ß SA Þ ß absorption
• Concentration Gradient – during fasting, there is more of a gradient, and absorption proceeds much more quickly
• during fed state, drugs last longer but have lower plasma concentration (area under curve is the same)
• Other Considerations:
• temperature – cold reflex to absorb more quickly (15 minutes with ice water, 45 minutes with lukewarm water)
• blood flow to gut – flow proportional to absorption – Ý blood flow Þ Ý rate of absorption