Welcome to Week 4 7.7 Oral Delivery II - edX · 2014-03-31 · Welcome to Week 4 Starting week four...

WelcometoWeek4

StartingweekfourvideoPlease watch the online video (46 seconds).

OPTIONAL‐Please participate in the online discussion forum.

7.7OralDeliveryII

MultipleoraldosesvideoPlease watch the online video (7 minutes, 34 seconds).

A condensed summary of this video can be found in the Video summary page.


CalculatingCpforanoraldrugBackground: The Cp of an oral drug is equal to the sum of the remaining drug from all the previous

doses administered to a patient.

Instructions: Read the passage below on calculating Cp for a drug and use the information to answer

the assessment questions that follow.

Learning Goals: To understand better how to determine Cp values for oral drugs at different time

points.

The Cp for an oral drug dose can be calculated at any time with the formula below if all the variables

are known.

Any reference with pharmacokinetic parameters on drugs will list bioavailabilty (F), volume of

distribution (Vd), half‐life (t1/2), and tmax, among others. kel can be calculated from t1/2. kab can be

estimated from tmax and kel (with some trial and error). With these parameters in hand, one can

calculate Cp at any time.

In order to determine Cp from many doses, one must calculate the Cp from each dose and add them

together. An important idea to remember is that the time of each dose is different. For example, if

a drug is dosed every 4 hours, then at 10 hours, Cpdose 1 would be calculated at the full time of 10

hours, but Cpdose 2 would be calculated at only 6 hours, and Cpdose 3 would be calculated at just 2

hours.

Please complete the online exercise.


ComplexitiesofdosingBackground: A successful dosing regimen usually involves administering a drug so that the

concentration of the drug remains within a window that provides a therapeutic effect without

demonstrating toxic effects.

Instructions: Read the case study on daptomycin, a drug that poses particularly difficult dosing

challenges.

Learning Goal: To gain exposure to more subtle issues surrounding the dosing of drugs.

Daptomycin is a large antibiotic. Daptomycin violates Lipinski's rules in just about every way

possible. Its molecular weight is 1,620 g/mol, well above the 500 g/mol limit of

Lipinski. Daptomycin also has far more than 5 hydrogen bond donors and 10 hydrogen bond

acceptors. Based on these traits, one might expect that daptomycin has a very low oral

bioavailability. That expectation is correct. Daptomycin cannot be formulated as an oral drug and is

instead administered intravenously. (See structure on following page.)

The antibacterial activity of daptomycin was originally discovered by scientists at Eli Lilly in the

1980s. The therapeutic effect of daptomycin is accompanied with toxicity to muscle

tissues. Unfortunately, the concentrations required for the antibacterial activity of daptomycin are

very similar to those that cause muscle toxicity.

Researchers at Eli Lilly explored several options for administering daptomycin and ultimately

focused upon a twice daily IV regimen. The hope was that a twice daily dosing would provide a

narrower range for Cp in the patient. By hitting a narrow Cp range, the drug may be able to hit

concentrations ideal for antibacterial activity and yet avoid or minimize the toxic effects.

A representation of Cp vs. time for both once daily (black line) and twice daily (red line) dosing is

shown below. Note that the twice daily schedule does keep Cp of daptomycin within a tighter range.

Unfortunately, researchers at Eli Lilly were unable to separate satisfactorily the antibacterial and

toxic effects of daptomycin. Eli Lilly closed their daptomycin research program. Another company,

Cubist, expressed interest in reviving the project. Eli Lilly then entered an agreement with Cubist,

and Cubist started its own research program in daptomycin in 1997.

This type of arrangement is common between drug companies. Large companies often have more

potential projects than available resources. Projects that are not making progress will be shelved to

free resources for more promising ones. Partnering with another company allows more projects to

be in development. If the shared project is successful, then both companies will share in the profits.

The drug discovery group at Cubist pursued a once daily dosing regimen for daptomycin. Instead of

minimizing the peak Cp values of daptomycin with twice daily dosing, Cubist's approach emphasized

the deeper Cp troughs of a once daily dosing. Cubist found that the muscle toxicity effects could be

minimized without sacrificing antibacterial activity. One possible interpretation is that the deeper

dips in Cp in the once daily regimen allow the muscles to recover periodically from the toxic effects

of the drug.

Cubist obtained a patent on their specific and novel dosing schedule which was counter to the

prevailing logic on daptomycin. Even though the composition of matter patent on daptomycin has

expired, generic manufacturers have been excluded from the market because of Cubist's dosing

patent.

The case of daptomycin demonstrates how each drug brings its unique challenges to drug

discovery. The therapeutic and toxic levels of each drug create new issues that must be addressed

by medicinal chemists.


7.8CLandVdRevisited

CLvs.VdplotsvideoPlease watch the online video (7 minutes, 27 seconds).



ModifyingstructurestoimprovePKBackground: A CL vs. Vd plot is an excellent tool for providing insight into how a drug's structure

might be modified in order to optimize its pharmacokinetics.

Instructions: Answer the questions below.

Learning Goal: To learn how to modify a drug or lead in order to achieve desired pharmacokinetic

properties.

Daptomycin is a large antibiotic. Daptomycin violates Lipinski's rules in just about every way

possible. Its molecular weight is 1,620 g/mol, well above the 500 g/mol limit of

Lipinski. Daptomycin also has far more than 5 hydrogen bond donors and 10 hydrogen bond

acceptors. Based on these traits, one might expect that daptomycin has a very low oral

bioavailability. That expectation is correct. Daptomycin cannot be formulated as an oral drug and is

instead administered intravenously. (See structure on following page.)



Chapter8‐Metabolism

IntroductiontoChapter8Chapter 8 contains six subsections.

Introduction

Phase I Pt 1

Phase I Pt 2

Phase II

Metabolite Issues

Prodrugs

Upon completing this chapter, you should understand the common types of drug metabolism

reactions that occur in the body and how to recognize and predict those reactions. You should also

recognize the complications that metabolites introduce to drug discovery based on demographic

difference and biological activity of the metabolites. Finally, you will see drug metabolism as an

exploitable process to improve the bioavailability of certain drugs.


8.1Introduction

MetabolismandVdvideoPlease watch the online video (7 minutes, 9 seconds).



ComparingmetabolitesBackground: When drugs are metabolized, the resulting metabolites are typically (but not always)

more polar than the original drug. One simple method for comparing the polarity of two

compounds is through lipophilicity, log P. In general, compounds with a lower lipophilicity (lower

log P), have a lower Vd and a shorter half‐life.

Instructions: Use data from the DrugBank (http://www.drugbank.ca/)to answer the questions

below.

Learning Goal: To understand more fully how metabolism can affect a drug and its metabolites in

terms of polarity and Vd.



8.2PhaseIPtI

OxidationvideoPlease watch the online video (6 minutes, 52 seconds).



OmegaoxidationBackground: Most oxidations of sp3 hybridized carbons occur adjacent to a nitrogen or oxygen atom

and cause dealkylation of the nitrogen or oxygen.

Instructions: Read the passage below for an example of another type of sp3 hybridized carbon

oxidation.

Learning Goal: To see another somewhat common type of Phase I oxidation.

Oxidations of simple sp3 hybridized carbon atoms are less rapid because the oxidation is not

activated by an adjacent oxygen or nitrogen atom. Simple alkyl chains can regardless undergo

metabolism in the body. These oxidations are called ω‐oxidations (omega oxidations).

One classic example of an ω‐oxidation was seen in the previous subsection. Terfenadine, an

antihistamine, undergoes ω‐oxidation on one of the tert‐butyl carbons. The C‐H bond is presumably

oxidized to an alcohol, which is rapidly oxidized to an aldehyde and then the acid. Interestingly, the

acid metabolite is itself also an antihistamine drug.

Another example of an ω‐oxidation can be found in the antidiabetic chlorpropamide. The propyl

chain in chlorpropamide actually undergoes two different ω‐oxidations. One is on the end of the

propyl chain. This is a true ω‐oxidation as it occurs on the end (omega) of the chain. The other is an

oxidation on the second‐to‐last carbon. This is formally called an ω‐1‐oxidation because it occurs

one carbon removed from the end of the chain.

While ω‐oxidations are less common than other types of Phase I metabolic reactions, they are

encountered with some regularity.


PredictingphaseImetabolitesBackground: Based on the functional groups in a molecule, the most likely metabolites of a drug can

often be predicted.

Instructions: In the questions below, predict likely structures of metabolites of mepyramine, one of

the early antihistamine drugs. Drawing the metabolite structures will require you to watch a video

on the use of JSDraw, a chemistry drawing program.

Learning Goals: To learn how to use JSDraw and gain experience predicting metabolites.

JSDrawtutorialvideoPlease watch the online video (4 minutes, 33 seconds).



8.3PhaseIPtII

ReductionandhydrolysisvideoPlease watch the online video (3 minutes, 55 seconds).



PredictingphaseImetabolitesBackground: One can often predict the metabolites of a drug based on the drug's functional groups.

Instructions: In the questions below, predict likely phase I structures of metabolites of the indicated

drugs.

Learning Goal: To gain experience predicting phase I metabolites of a drug.



8.4PhaseII

ConjugationvideoPlease watch the online video (6 minutes, 41 seconds).



RoleofglutathioneBackground: Glutathione is a nucleophilic molecule that reactions with electrophilic molecules in

the liver.

Instructions: Read the passage below concerning how glutathione protects the liver and body from

being damaged by certain drugs.

Learning Goals: To understand better how the liver metabolizes drugs and the limits of the liver in

detoxification.

The liver breaks down drugs, primarily through its arsenal of oxidative CYP‐450 enzymes. The

process of oxidation involves the loss of electrons. As a molecule loses electrons, it becomes

electron poor and therefore more electrophilic. Strong electrophiles, which are often formed

through metabolic reactions, can be very damaging to cells. This raises a question... How can the

liver continuously perform oxidative reactions on drugs and other molecules without being

extensively damaged by electrophilic metabolites?

The answer is that the liver is protected by processes such as glutathione conjugation. Glutathione,

a natural nucleophile through its thiol group, reacts with strong electrophiles and sacrifices itself

before the liver tissue is damaged. The protection of the liver is only limited by the liver's stores of

glutathione. The concentration of glutathione in the liver is around 5 mM. If a person ingests too

much of a compound that reacts with glutathione, then once the glutathione reserves are

consumed, the liver will be damaged. It is for this reason that drug overdoses often lead to

extensive liver damage

PredictingphaseIImetabolitesBackground: Based on the functional groups in a molecule, the metabolites of a drug can often be

predicted.

Instructions: In the questions below, predict likely structures of phase II metabolites of the drugs

that are shown.

Learning Goal: To gain experience predicting phase II metabolites.



8.5MetabolismIssues

MetabolisminhibitionvideoPlease watch the online video (7 minutes, 24 seconds).



Casestudy‐cimetidineBackground: Drugs that inhibit any of the CYP enzymes have the potential to interfere with the

metabolism of other drugs. This type of drug interaction can cause safety problems and affect the

marketability of a drug.

Instructions: Read the passage below about CYP inhibition of cimetidine.

Learning Goals: To learn about the implications of CYP inhibition of a drug.

Cimetidine is a histamine H2‐receptor antagonist and represented a first‐in‐class drug for the

treatment of acid reflux. Cimetidine was marketed in the United States in 1979 under the brand

name Tagamet. Cimetidine met great success and enjoyed high sales.

In 1983 another histamine H2‐receptor antagonist, ranitidine, reached the market in the United

States. Ranitidine, sold under the name of Zantac, has a structure that is strikingly similar to

cimeditine. Ranitidine is an example of a me‐too drug. Me‐too drugs tend to follow quickly behind

a first‐in‐class drug and have similar structures. The composition of matter patents surrounding

cimetidine emphasized the importance of the imidazole ring for the activity of histamine H2‐

receptor antagonists. The researchers who discovered ranitidine were able to use a furan ring in

place of imidazole and still maintain activity.

A me‐too drug rarely matches the profitability of the first drug in a class. The first drug dominates

the market, and the me‐too drug lags behind. Ranitidine, however, surpassed the market share of

cimetidine in a just a few years. The reason behind the success of ranitidine was CYP inhibition by

cimetidine. Cimetidine inhibits several forms of CYP, including CYP1A2, CYP2D6, and, most

importantly, CYP3A4. Cimetidine therefore has a long list of drug interactions. While ranitidine also

inhibits several CYP forms, ranitidine is a less potent inhibitor than cimetidine. Many patients who

experienced complications with cimetidine switched to ranitidine

FactorsinmetabolismBackground: Based on the functional groups in a molecule, the metabolites of a drug can often be

predicted.

Instructions: Genetic differences can play a significant role in how a drug is metabolized in one

patient or another. Other factors also are important.

Learning Goal: To learn how health and age affect drug metabolism.

While genetic differences can affect drug metabolism, metabolic differences between people of

different races are typically very small, even negligible. Gender is yet another factor that is normally

of little importance when discussing metabolism. Other factors, including age and health, are far

more influential with regard to drug metabolism. The compound theophylline, a drug sometimes

used to treat asthma, highlights these differences.1

Age can greatly influence drug metabolism. Below is a table showing how half‐life can vary with age

for theophylline. Bear in mind that theophylline is cleared primarily by the liver, so changes in half‐

life reflect changes in liver activity.

age half‐life (h)

infants (1‐2 days) 25.7

infants (3‐30 weeks) 11.0

children (1‐4 years) 3.4

children (6‐17 years) 3.7

adults (18‐60 years) 8.7

elderly (>60 years) 9.8

The variability of the half‐life of theophylline shows how metabolism changes with age. Very young

infants are not completely developed metabolically, so the half‐life is long. By an age of 12 months,

children are metabolically extremely active and the half‐life of theophylline drops below 4

hours. Once a person matures physically, the half‐life lengthens to just under 9 hours. Late in life,

as a person's metabolism gradually slows, the half‐life of theophylline also lengthens slightly.

Physical health can also affect the half‐life of a drug. Below is a table showing how half‐life can vary

with health or physical condition for theophylline.

condition half‐life (h)

liver cirrhosis 32.0

hepatitis 19.2

pregnancy (1st trimester) 8.5

pregnancy (2nd trimester) 8.8

pregnancy (3rd trimester) 13.0

sepsis 18.8

hypothyroid 11.6

hyperthyroid 4.5

Conditions that negatively affect or place stress on the liver (cirrhosis, hepatitis, late pregnancy,

blood infection, and hypothyroid) lengthen the half‐life of theophylline. Hyperthyroidism, a

condition in which a patient has an accelerated metabolism (among other things), causes a dramatic

decrease in half‐life.

Another condition that frequently affects a drug's half‐life is diabetes. Advanced diabetic patients

often have limited kidney function. Renal clearance is diminished, and drugs that rely on the

kidneys for clearance have lengthened half‐lives.

1. Murray, L., Sr. (Ed.). Physician's Desk Reference (58th ed.) Montvale, NJ: Thomson PDR, 2004.


PharmacokineticscatterBackground: Drugs are listed with distinct pharmacokinetic parameters. These parameters provide

a sense of precision for a drug and exactly how it behaves.

Instructions: Read the short passage below and review the figures in the linked article

(http://aac.asm.org/content/50/7/2281.full) in Antimicrobial Agents and Chemotherapy and answer

the questions that follow.

Learning Goal: To appreciate the broad variability in the action of drugs across different patients.

One of the drugs used to prevent and treat malaria is mefloquine. Mefloquine is administered orally

in its racemic form and is well absorbed. The drug is mostly excreted through the bile, meaning it is

absorbed, collected in the gall bladder, excreted in bile, and exits the body in feces. Compounds

found in the feces are often not absorbed, but in this case, the drug is indeed absorbed from the

gastrointestinal tract.

In a study on mefloquine dosing, 50 patients received 8 mg mefloquine per kg of body mass (8

mg/kg) on Day 0, Day 1, and Day 2 of the study. Patients were then monitored for approximately

one month for their Cp levels of mefloquine. From this data, the pharmacokinetic parameters of

mefloquine could be determined.

The ideal Cp‐time curve (http://aac.asm.org/content/50/7/2281/F2.expansion.html) shows a

smooth, predictable relationship between Cp and time.

The scatter plot (http://aac.asm.org/content/50/7/2281/F1.expansion.html) of the experimental

data gives a much less convincing relationship based on a visual inspection. The scatter seen in the

experimental graph is representative of experimental pharmacokinetic data. The behavior of a drug

can vary wildly among different patients. It is for this reason, in part, that drug must have a wide

therapeutic window.



8.6Prodrugs

ProdrugsvideoPlease watch the online video (6 minutes, 43 seconds).



Casestudy‐antiplateletdrugsBackground: Prodrugs are compounds that are converted in the body to the biologically active form

of the molecule. Many prodrugs are administered in an inactive form because the active form is not

well absorbed.

Instructions: Read the passage below about two antiplatelet drugs, clopidogrel and prosugrel.

Learning Goal: To understand that metabolic activation of a prodrug can have problematic genetic

variability across a broad patient population.

Antiplatelet drugs are compounds that inhibit clot formation and therefore reduce the incidence of

stroke, heart attacks, and other clot‐dependent conditions. Antiplatelet drugs can fall into several

different classes, one of which is the adenosine diphosphate receptor inhibitors. Two examples of

adenosine diphosphate receptor inhibitors are clopidogrel and prasugrel. Both clopidogrel and

prasugrel are prodrugs.

Clopidogrel was approved by the US FDA in 1997. The compound is activated in the body by phase I

oxidation of the thiophene ring. One of the sp2 hybridized carbons in the ring is oxidized by

CYP2C19. The resulting hydroxythiophene is unstable and hydrolyzes to give the ring‐opened, active

form of the drug.

Around 5‐10% of the US population have a genetic variation in CYP2C19 that renders the enzyme

less active in the metabolism of clopidogrel. For these patients clopidogrel is not activated properly

in the body, and the patients do not have therapeutically effective levels of the metabolite. Because

of the potential lack of effect of prosugrel, the FDA added labeling in 2010 to clopidogrel packing to

indicate the possible lack of effectiveness of the drug. This so‐called black box warning raises safety

awareness and concerns for both prescribing physicians and patients.

Prasugrel is in the same drug class as clopidogrel and was approved in 2009. Prasugrel is nearly

identical in structure to clopidogrel. The major difference is that the thiophene ring already bears

an oxygen. The ring is essentially oxidized in its administered form. In the body the drug is activated

by hydrolysis of the acetate ester to form the hydroxythiophene metabolite, which forms the active

form of the drug.

Prasugrel, which is activated by plasma lipases instead of CYP2C19, shows fewer variations in how it

is metabolized across broad populations of patients. For this reason, prasugrel is not packaged with

black box warnings. Prasugrel is an example of how understanding metabolic issues of a drug

allowed the clever design of a safer version of what is otherwise a nearly identical drug.


DrawingprodrugsBackground: Prodrugs are compounds that are converted in the body to the biologically active form

of the molecule.

Instructions: Do the problems below by predicting the structure of the prodrug based on the

structure of its active metabolite.

Learning Goal: To recognize how particular functional groups can be formed in the body through

metabolic reactions.



Survey

Week4SurveyPlease complete the very brief online survey, which should take less than one minute.

Examination2

SecondExaminationThe exam is open book and open notes. All questions may be attempted once, so be certain of your

answer before submitting it. There are ten questions. Each is its own unit within the Examination 2

subsection.

Remember that you are bound by the honor code. No postings to the forum concerning the exam

are allowed. Furthermore, you must work on the examination independently

ProblemsPlease complete the online problems in Examination 2.

Welcome to Week 4 7.7 Oral Delivery II - edX · 2014-03-31 · Welcome to Week 4 Starting week four...

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