Pharmacokinetics

Sutomo TanzilDept.of Pharmacology, Faculty of Medicine, Sriwijaya University

The movement of drug molecules across cellular barriers (1)

To traverse cellular barriers (e.g.GI mucosa, renal tubule, blood-brain barrier, placenta), drugs have to cross lipid membranes.

Drugs cross lipid membranes mainly (a) by passive diffusional transfer and (b) carrier-mediated transfer

The main factor t/ determines the rate of passive diffusional transfer across membranes is a drug’s lipid solubility. Molecular weight is a less important factor.

The movement of drug molecules across cellular barriers (2)

With weak acids or bases only the unionised forms can diffuse across lipid membrane; this gives rise to pH partition.

pH partition means t/ weak acids tend to accumulate in compartments of relatively high pH, whereas weak bases do the reverse.(ion trapping phenomenon)

Carrier-mediated transport is important for some drugs t/ are chemically related to endogenous substances.

Passive diffusional transfer

Lipid solubility pH & ionization Not selective, no energy required,

not saturable, cannot be inhibited pH partition & ion trapping Most drugs across cell membrane

by this transfer.

Carrier-mediated Transport(CMT)

Carrier molecule: a protein which binds molecules or ions, and releases them on the other side of the membrane.

CMT may operate without energy by facilitating the process of transfer in the direction of its electrochemical gradient and the mechanism is called facilitated diffusion. Eg.the transfer of glucose across a muscle cell membrane mediated by GLUT4.

CMT can also occur against an electrochemical gradient and is called active transport. Eg.: sodium pumps, Na-Ca exchange.

CMT shows the characteristic of saturation, and can be inhibited competitively by a second ligand that binds the carrier.

Intravenous administration (i.v)

Absorption circumvented w/ potentially immediate effects. Suitable for large volume & for irritating substances.

Valuable for emergency use Permits titration of dosage Usually required for high-molecular weight protein

and peptide drugs Increased risk of adverse effects The solution must be injected slowly as a rule Not suitable for oily solutions or poorly soluble

substances.

Subcutaneous administration (s.c)

Absorption is prompt, from aqueous solution, slow and sustained from repository preparations.

Suitable for poorly soluble suspensions and for instillation of slow-release implants

Not suitable for large volumes Possible pain or necrosis from

irritating substances.

Intramuscular administration (i.m.)

Absorption is prompt from aqueous solution, slow and sustained from repository preparations.

Suitable for moderate volumes, oily vehicles, and some irritating substances.

Precluded during anticoagulant therapy, and may interfere w/ interpretation of certain diagnostic tests (e.g.creatine kinase)

Oral/Enteral administration

Absorption is variable, depends on many factors

Most common method of drug adminis-tration.It is also the safest,most conve-nient, and most economical. Disadvantages include limitation of absorption of some drugs because of their physical characteristics (eg.water solubility), it also requires patient compliance

Bioavailability is potentially erratic and incomplete.

Drug absorption and bioavailability

Drugs w/ low lipid solubility are poorly absorbed from the gut.

A few drugs (eg.levodopa) are absorbed by CMT. Absorption from the gut depends on: -GI motility, -GI pH,

particle size, -physicochemical interaction with gut contents (eg. Ca and tetracycline antibiotics)

Bioavailability is the fraction of an ingested dose of a drug that gains acces to the systemic circulation. It may be low because absorption is incomplete, or because the drug is metabolised in the gut wall or liver before reaching the systemic circulation.

Bioequivalence implies that if one formulation of a drug is substituted for another no clinical untoward consequences will ensue.

Methods for delaying absorption

Addition of adrenaline (epinephrine) to a local anesthetic

‘slow-release’ form : procaine-penicillin,medroxyprogesterone acetate, testosterone propionat, flufenazine decanoate

Insulin zinc suspensions Subcutaneous implantation of solid

pellets

Drug distribution (Vd)

Vd : the volume of plasma that would contain the total body content of the drug at a concentration equal to that in the plasma.

Lipid insoluble drugs :confined to plasma and the interstitial fluids; most do not enter the brain .

Lipid-soluble drugs reach all compartments, and may accumulate in fat.

For drugs that accumulate outside the plasma compartment (eg. in fat, or being bound to tissues) Vd may exceed total body volume.

Drug metabolism

Phase I reactions:oxidation,reduction & hydrolysis. These usually form more reactive products,sometimes pharmacologically active, toxic or carcinogenic. Phase I oftenly involve cytochrome P450 enzymes.

Phase II reactions : conjugation (eg.glucuronidation) of a reactive group (often inserted during phase I) and form inactive and readily excretable products.

Some conjugated products are excreted via bile, are reactivated in the intestine and then reabsorbed.

Induction of enzymes by other drugs and chemicals can greatly accelerate hepatic drug metabolism.

Some drugs show rapid “first-pass” hepatic metabolism, and thus poor oral bioavailability.

Inhibition of P450

Ketoconazole (an antifungal) which forms a complex with CYP3A4, causes a non-competitive inhibition with a risk of a fatal cardiac arrhythmia if the drug is given concomitantly with terfenadine (an antihistamine).

Induction of P450

Enzyme inducers: ethanol,rifampicin, carbamazepine,increase the activity of microsomal oxidase and conjugating systems when administered repeatedly

Glomerular filtration

Drugs w/ MW <20,000 can cross the glomerular filter, but plasma albumin (MW 68,000) cannot.

If a drugs is highly bound to plasma albumin (eg. Warfarin 98% bound), its concentration in glomerular filtrate is very low (only 2% warfarin).

Tubular secretion

20% of renal plasma flow is filtered through the glomerulus, leaving 80% of the delivered drug to pass on to the peritubular capillaries of the proximal tubule. Here drug molecules are transferred to the tubular lumen by 2 independent carrier systems.One of these transport acidic drugs, while the other handles organic bases.

These active transport can transport drug molecules against an electrochemical gradient and can, therefore , reduce the plasma concentration nearly to zero. Since 80% of the drug delivered to the kidney is presented to the carrier, tubular secretion is potentially the most effective mechanism of renal drug elimination, even when most of the drug is bound to plasma protein (e.g. penicillin)

Diffusion across the renal tubule

As the glomerular filtrate traverses the tubule, water is reabsorbed, so that the volume of urine only about 1% of the filtrate.

High-lipid soluble drugs are excreted slowly,while polar &low lipid soluble drugs remain in the tubule & its concentration in the urine is 100 times >than in plasma.

The ion-trapping effect :a basic drug is more rapidly excreted in an acid urine, because the low pH within the tubule favours ionization and thus inhibits reabsorption.

Biliary excretion and enterohepatic circulation

Liver cells transfer various substances, including drugs, from plasma to bile by means of transport systems similar to those of the renal tubule and which involve P-glycoprotein.

Drug conjugates (particularly glucoronides) are concentrated in the bile and delivered to the intestine where the glucuronide is usually hydrolysed, releasing active drug once more. Free drugs can then be reabsorbed and the cycle repeated (enterohepatic circulation).

Examples :morphine, ethinylestradiol, and rifampicin.

Effect of variation in rate of absorption

Absorption rate constant , kabs , is directly proportional to the amount of drug which is still unabsorbed

Area under the curve (AUC) is directly proportional to the total amount of drug that enters the plasma.

Oral Bioavailability = AUCoral / AUCiv

Intravenous bioavailability = 100%

Saturation kinetics

E.g. Ethanol, phenytoin, salicylate The rate of disappearance of ethanol

from the plasma is constant at about 4 mmol/L per hour irrespective of its plasma concentration.

Also oftenly termed as ‘zero-order kinetics’

The rate of drug metabolism by hepatic enzymes reaches a maximum at low plasma concentration.

References and Further Reading

Brunton,L.L.; et al.(2006). Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 11th Ed.,McGraw-Hill Medical Publishing Division, USA.

Katzung,B.G.(2007).Basic&Clinical Pharmacology,10th Ed., McGraw-Hill,USA.

Rang & Dale (2003). Pharmacology, 5th Ed.,Churchill Livingstone, London, UK.

Staf Pengajar Dep.Farmakologi FK Unsri (2008). Kumpulan Kuliah Farmakologi, Edisi 2, EGC,Jakarta.