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1. Pharmacokinetics drug-drug interaction
Prepared by : OUTLINE :

2. It is irreversible transfer of a drug from its site of administration
to the bloodstream.
Rate and Efficiency of absorption depends on route of administration
For IV > absorption is complete 100% = highest bioavailability
For other routes > only partial absorption = lower bio availability
A change in a drug’s effect on the body when the drug is taken together with a
second drug. A drug-drug interaction can delay, decrease, or enhance
absorption of either drug. This can decrease or increase the action of either or
both drugs or cause adverse effects.

4. Pinocytosis is a form of endocytosis involving fluids containing many solutes. In humans, this process
occurs in cells lining the small intestine and is used primarily for absorption of fat droplets.
Engulfment of a drug moecule by the cell membrane & transport into the cell by pinching off the
drug-filled vesicle
: Vitamin B12
Reverse of Endocytosis – used by cells to secrete substances out of the cell by similar process of
vesicle formation
: Norepinephrine (NE) & other Neurotransmitters (Ach) – stored in membrane-bound
vesicles in the nerve terminal & released by exocytosis
If 2 drugs have similar structures & absorbed by active transport – compete on the same
transport carrier & one of higher affinity will absorbedwhile other one is retained
Drug to be readily absorbed should be largely (mostly) lipid soluble (NotCompletely )

5. - Absorption interactions involve changes in either the rate or extent of absorption.
- Drugs that either delay(e.g. anticholinergic drugs) or enhance (e.g. prokinetic drugs) the
rate at which this occurs will influence the rate of rise in plasma concentrationbut not
the totalamount of drug absorbed.
- The extent of absorption can be influenced by second drugsthat bind to form insoluble
complexes or chelates (e.g.aluminium containing antacids binding withciprofloxacin).
Wrong choice of drug
Wrong dosage
Wrong route of administration
Errors in taking the drug

6. It is the fraction of administered drugthat reaches the systemic circulation in anunchanged form (unmetabolized)
If 100 mg of a drug is administered orlly& 70 mg of this drugare absorbed unchnged
Bioavailability is .7 or 70% [Reference route is IV]
If drug is rapidly metabolizedby liver >
decrese amountof unchanged drug >
decrease bioavailability
First-base metabolism
Pencilin G – is unstable in the ph of the
gastric contents
Insulin – is destroyed in the git by
degradative enzymes
Chemical instability
Completelylipidsoulable drugs and also
highly water soluable drugs are poorly
absorbed– decrease bioavailability
Drug solubility
Particle size , salt form , crystal
polymorphism , enteric coating > alter
rate of absorption
Drug formation

7. Itallbeganwith cheese
Duringthe 1960s, hypertensive crises, in some cases fatal, were reported in several patients
treated for depression with monoamine oxidase(MAO) inhibitors, after they had eaten certain
cheeses.
It was shown thatthese cheeses had a very high contentof tyramine, an amine with pressor
effects, and their intestinal metabolism was inhibitedby MAO inhibitors.
It was calculated that 10 mg oral tyramine was enough to evoke a marked pressor effect in
patients with inhibited MAO. The highestconcentrationof tyramine (3 mg.g−1) was foundin a
Swedish blue cheese, ingestedby a patienttreated with nialamide who subsequently died from
cerebral hemorrhage.
It was later found that the MAO inhibitors alsointeractwith
other psychotropicdrugs.

8. Usually, drugs are transported through a binding to plasma and tissues
proteins.
The most important are albumin, α1-acid glycoprotein, and lipoproteins.
Acidic drugs are usually bound more extensively to albumin, while
basic drugs are usually bound more extensively to α1-acid glycoprotein,
lipoproteins, or both.
Only unbound drug is available for passive diffusion to extravascular or
tissue sites and typically determines drug concentration at the active site
and thus its efficacy.

9. Also, there are several locations for drugs to bind to RBCs,
including to hemoglobin and the plasma membrane.
Medications that commonly bind to RBCs include
barbiturates, chlorpromazine, imipramine, and phenytoin.

10. Antibiotics Ceftriaxone, doxycycline, ertapenem
Antidepressants Duloxetine, fluoxetine, nortriptyline, sertraline
Antipsychotics Chlorpromazine, clozapine, haloperidol
Anxiolytics Chlordiazepoxide, diazepam, lorazepam
Cardiac Amiodarone, bumetanide, furosemide, nicardipine, verapamil, w arfarin
Chemotherapy Paclitaxel, tamoxifen
Diabetes Glipizide
Pain Bupivacaine, buprenorphine, ibuprofen
Seizure Phenytoin, valproic acid
Source: Reference 1

11. A typical pharmacological displacement can be observed when
warfarin and diclofenac are co-administered.
Warfarin and diclofenac have same affinity for albumin,
therefore the administration of diclofenac to a patient treated
chronically with warfarin results in displacement of latter from
its binding site.
The increase in plasma concentration of free warfarin
causes the development of serious hemorrhagic reactions.

12. Close clinical and laboratory observation for hematologic
complications is recommended. Patients should be advised to
promptly report any signs of bleeding to their doctor (unusual
bleeding or bruising).
If it is not necessary to use NSAIDS, they can be replaced.

13. Carbapenem class of antibiotics, which includes ertapenem, interacts
with divalproex (valproic acid [VPA]).
Proposed mechanisms include a lowering of VPA serum levels due to a
redistribution of the VPA onto the RBCs due to carbapenem.
Seizures have been reported among patients receiving this combination.

14. Another broad-spectrum antibiotic, such as piperacillin / tazobactam,
could be used.
If it is medically necessary to administer VPA and
ertapenem, closely monitor VPA levels.

15. Salicylic acid increases the levels of Methotrexate causing
hepatotoxicity, bone marrow suppression, nausea, fatigue,
alopecia, oral ulcers, and very rarely pulmonary fibrosis.

16. If drugA induces the enzyme’s activity , then blood plasma conc of drugB will quicklyfall as
its inactivation will take place more rapidly . As a result, will cause a decreasein the drug’s
effect. (subtheraputicdose)
Enzyme inducers :
Phenytoin , rifampicin , phenobarbital , carbamazepine , smoking
Common interactions with :
Oral hypoglycemic drugs and oral contraceptives
Examples :
*Rifampicin with contraceptive >> induce pregnancy
*phenytoin with Oral hypoglycemic>> hypoglycemia
*phenobarbital will cause induction of self metabolism >> dependence

17. If drug A inhibits the enzyme’s activity , then drug B willremain with
high levels in the plasma for longer as its in activation is slower . As a
result , will cause an increase in the drug’s effect (Toxicity)
Ketoconazole , metronidazole , cimetidine , erythromycin , ritonavir
Usually occur with narrow theraputic index drugs
Examples : warfarin , theophylline , digoxin
* Cimetidine with warfarin >> hemorrhage solved by drug monitoring

18. The kidney is the organ responsible for the elimination of drugs
and their metabolites.
The interaction may occur for a mechanism of competition at
the level of active tubular secretion, where two or more drugs
use the same transport system.
An example is given by NSAIDs that determine the appearance of
toxic effects caused by methotrexate when the renal excretion of
the anti-proliferative drug is blocked

19. Cimetidine, a histamine H2-receptor
antagonist, is a classic inhibitor of
renal OC secretion
CimetidineMetforminhOCT2, hMATE1,
and hMATE2-K
PPIs (i.e.,
omeprazole,pantoprazole)
Metformin
Pyrimethamine is an antiparasitic
commonly used for malarial
infection.
PyrimethamineMetformin
Dolutegravir is a newly approved
anti-HIV drug
DolutegravirMetformin
Probenecidis the prototype
inhibitor for the renal organic
anion secretion system
ProbenecidhOAT1 and hOAT3
Furosemide is a loop diuretic, which
exerts its pharmacological effects by
inhibiting Na+-K+-2Cl– cotransporter
ProbenecidFurosemide
Cidofovir is an acyclic nucleotide
analog used in the treatment of
cytomegalovirus infection of the
eye.
ProbenecidCidofovir

20. Fexofenadine, an active metabolite of
terfenadine, is a selective histamine
H1 receptor antagonist used for the
treatment of allergic rhinitis and chronic
idiopathic urticaria.
ProbenecidFexofenadine
probenecid was first developed as a
penicillin-sparing agent to prevent the
rapid urinary loss of the antibiotic
ProbenecidPenicillin
methotrexate
Anti-arrhythmicQuinidineDigoxinP-gp
calcium-channel blockersverapamilDigoxin
clarithromycinDigoxin