A3. Drug absorption, distribution and bioavailability. Membrane transport mechanisms.

Question 1

What is Pharmacokinetics?

Answer 1

Pharmacokinetics is the study of how the body affects administered substances through the following processes: (ADME mnemonic usually used) • Absorption • Distribution • Metabolism • Excretion

Question 2

List the characteristics of drug administration related to pharmacokinetics.

Answer 2

• Route of administration • Dose • Frequency of administration • Duration of treatment

Question 3

4 membrane transport mechanisms for drug absorption:

Answer 3

1. Aqueous Diffusion occurs more with molecules that are small (< 0.4 nm) and ionized diffuse through pores in the epithelial membrane and endothelial layers 2. Lipid Diffusion Determined by concentration gradient, “lipid/aqueous partition coefficient” of drug, and membrane characteristics o Lipid-soluble drugs are usually non-ionized / uncharged. (Aminogylcosides are an exception, apparently they are lipid-insoluble even in non-ionized form) 3. Carrier-Mediated Transport: 2 types: facilitated diffusion and active transport 3 characteristics: selective, saturable, and able to be inhibited Primarily applies to molecules which are non-lipid-soluble, xenobiotics, and endogenous large molecules i. examples: peptides, glucose, L-DOPA 4. Endo- / Exocytosis endocytosis: large molecules such as iron/B12 complexed with proteins, or anti-cancer drugs bound to monoclonal antibodies exocytosis: neurotransmitter release from vesicles, histamine from mast cells

Question 4

Main Transporter “Superfamilies”:

Answer 4

1. ATP-binding cassette (ABC) - functions mostly in efflux using ATP; (7 families) a. Main roles: i. excretion of drugs into urine, bile, and intestines ii. drug resistance in tumor chemotherapy b. some important types: i. Multidrug Resistance Protein (MDR), AKA P-glycoprotein ▪ Occurs in intestinal epithelium, blood-brain barrier, placenta, and testis. Example: loperamide is an opioid which has no CNS effects because P-glycoprotein expels it first ▪ Inhibitors: clarithromycin, ritonavir, nicardipin, grapefruit ii. Multidrug resistance-associated Protein (MRP) iii. BCRP, breast cancer resistance protein 2. Solute Carriers (SLC) - mostly influx (some efflux) using ion gradients; (48 families). Takes up small molecules into cells a. subfamilies: organic anion transporters (OAT, OATP) and organic cation transporters (OCT)

Question 5

Factors influencing absorption:

Answer 5

• pH • pH determines ionization of a drug. Ionized drugs absorb better in the acidic environments (e.g. the stomach). Weak bases absorb better in the small intestine. o Aspirin is an acid (acetylsalicylic acid) that absorbs better in the stomach. However, it tends to become trapped in gastric mucosal cells where the pH is more normal (7.4), thus can damage the gastric mucosa. • pH also determines the ability of a drug to be excreted o Increasing the urine pH will ionize weak acids to increase their excretion. NaHCO3 can be used to alkalinize the urine and improve weak acid excretion o Vice versa is also true: weak bases are excreted better in acidic urine. Can give NH4Cl to excrete weak base drugs more effectively. • Blood flow to absorption site - intestines receive more blood flow than stomach; shock decr. cutaneous flow + thus subcutaneous absorption) • Total surface area - intestinal villi -> high abs. • Contact time - diarrhea speeds intestinal transit, decr. absorption • P-glycoprotein - decreases absorption via efflux

Question 6

What are the different routes of administration?

Answer 6

• Oral • Sublingual / buccal: bypasses first pass metabolism • Parenteral: IV, IM, SC injections • Advantages: better absorbability, better bioavailability, more precise dose control • Disadvantages: difficult to reverse (no effect from charcoal), infection, may precipitate, usually has to be done in presence of a health care worker unless the patient is properly trained • Inhalation • Nasal • Eye drops • Topical • Intrathecal: injected into CSF (sometimes antibiotics for meningitis, some painkillers) • Rectal

Question 7

Distribution:

Answer 7

• Volume of Distribution: aka Vd. The theoretical volume that would be necessary to contain the total amount of an administered drug at the same concentration that it is found in the plasma • Vd = amount of drug in body / [drug] in plasma. Expressed in liters. • example: 100 mg of a drug is injected and then found to be at 5 mg/l in the plasma; with 4 L total plasma, the other 80 mg must be distributed elsewhere. if we assume that 80 mg is at the same concentration as in plasma, then the Vd is the volume of plasma (4 L) plus the 16 other liters needed to contain 80 mg at 5 mg/l … so Vd = 20 L total • comparison of the distribution of a drug with the volumes of fluid compartments of the body, to determine where it distributes generally • Vd < 5 L means drug distributes only in blood (if you work it out mathematically, the plasma concentration is almost the same as the amount in the body) • a larger Vd means it may distribute also in the interstitial fluid (Vd ~ 14L) or total body water (Vd ~ 42L) • Effect on half-life: Elimination depends on drug delivery to liver/kidneys via blood. A drug with high Vd has a low plasma concentration + thus is not well-delivered to these organs for elimination

Question 8

• Distribution of various body compartments

Answer 8

• Central compartments - good blood supply; plasma, brain, liver, lung, kidney, heart • Peripheral - poor blood supply; fat, skin, muscle • Deep - very poor blood supply; bone, cartilage, joint

Question 9

Where certain molecules tend to accumulate in the body:

Answer 9

• Total body water - small, water-soluble molecules (ethanol, phenytoin, diazepam) • Extracellular fluid - bigger water-soluble molecules (gentamycine, tubocurare) • blood - large / protein-bound molecules (heparin, insulin, warfarin) • fat - highly lipid-soluble (DDT, thiopental) • bone - ions (lead, fluoride, tetracyclines)

Question 10

Bioavailability:

Answer 10

the fraction of unchanged drug which reaches the systemic circulation after administration. • Influenced by: o First-pass metabolism: metabolism of a drug after oral administration before it can reach systemic circulation. ▪ Liver: probably the most important, alters many drugs ▪ Intestinalwall ▪ Stomach: for example degrades the original penicillin G ▪ Digestive enzymes: degrades peptide drugs, so they usually have to be given parenterally o Solubility - very hydrophilic drugs can’t cross membranes; very lipophilic drugs are insoluble in body fluids + don’t gain access to cell surfaces; mostly lipophilic but partly water soluble drugs are best absorbed o Chemical Stability - drugs degraded by gastric HCl or intestinal enzymes not absorbed well o Drug Formulation/Vehicle - particle size, salt form, crystal polymorphism, enteric coating, binders/dispersing agents (“excipients”) • differs by route of administration: IV 100%, IM 75-100%, Oral >5 but <100%, Rectal >30 but <100%, transdermal 80-100% • Determined by comparing the “area under curve” (AUC) of a plasma conc. vs. time graph when administered by the route in question vs. AUC when administered IV