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Bioavailability

Adapted by: Sereta Campbell-Elliott B. Pharm; M Pharm. Sc

Prepared By: Marcia Williams

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What is a drugs’ bioavailability?

- Rate and (relative) amount of a dose of a drug that reaches systemic circulation intact

May be affected by:- physiological factors- formulation/manufacturing factors- physicochemical properties of active

drug

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Assessment of Bioavailability

Cannot assess precise concentration at site of action

Assumption that conc. of drug in body fluids such as plasma, urine or saliva over a period of time after administration correlates with the clinical efficacy of the drug’s therapeutic action.

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Important parameters in bioavailability studies

Time to Peak (Tmax): the time after admin that it takes for the drug to reach Cmax. This is an indication of the rate of absorption.

Max. conc. Attained (Cmax): assesses whether conc. is in therapeutic range

Area Under the Curve (AUC): Total drug abs. - reflects changes in distr. metabolism & excret

Onset of Action: The time required to reach the MEC. following drug admin.

Duration of Action: The time period in which the plasma conc. Exceeds MEC.

Intensity: the difference in the MEC and Cmax.

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Important parameters in bioavailability studies (cont’d)

Absorption rate conctant (ka): assesses the

rate of drug absorption from a formulation

Minimum Effective Concentration (MEC): minimum plasma conc. that must be reached before achieving therapeutic effect.

Maximum Safe Concentration (MSC): the conc. above which toxic effects are seen.

Minimum Toxic Concentration (MTC): The minimum concentration at which the toxic effect of the drug is seen.

Therapeutic Range: Plasma conc. range bet. MEC and MSC.

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Illustration of bioavailability variables

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Representation of Bioavailability Data

Construction of plasma concentration vs time curve.

Initial rise in curve indicates that drug is absorbed at a faster rate than it is metabolized or excreted. (absorption phase)

It continues to rise until a peak conc. is obtained (Cmax) - rate of absorption = rate of excretion.

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Representation of Bioavailability Data(cont’d)

At the beginning of the descending portion of the curve, both absorption and elimination is taking place - elimination is faster.

After a time absorption ceases and the conc. of drug in plasma is determined only by the rate of elimination. (the elimination phase of the curve)

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AUC Measurement

Most common method is the trapezoid method

For each trapezoid [AUC] = C n-1 + Cn (tn – tn-1) 2

AUC total = AUC extrap + AUC 0-t

where AUC extrap = C last /k el

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Illustration of Trapezoid Method from graph

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AUC Measurement

Time (hr)

Plasma Conc

(g/ml)

0.5 38.9

1 30.3

2 18.4

3 11.1

4 6.77

5 4.10

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Absolute and Relative Bioavailability

Absolute Bioavailability (BA)The fraction of the administered dose which is

absorbed intact into the systemic circulation. BA = (Auctab/AUVIV) x 100%F = fraction of drug absorbed

Relative Bioavailability (BR)A measure of the fraction of a given drug that is

absorbed intact into the systemic circulation from a dosage form relative to a recognized standard dosage form of that drug.

BR = (AUCtest(oral)/AUCstd,(oral)) x 100%

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Urinary Drug Excretion Data

Measures conc. of intact drug &/or its metabolite in the urine.

Collection of urine is easier and less unpleasant for the patient than collection of blood samples.

Conc. Of drug in urine is higher than in blood.Lower conc. of protein & other endogenous

substances makes drug assay easier.Useful only if drug is extensively excreted in the

urine and rate of excretion is proportional to the conc. of drug in plasma.

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Urinary Drug Excretion Data (cont’d)

Drug excreted in urine will not be proportional to conc. in plasma if the drug or its metabolites are:

excreted by active transport.weakly acidic or weakly basic - since rate of

excretion will depend on the pH of the urine.Urine flow determines excretion rate.Er (mcg/hr) = Amt of drug

time interval

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Urine Data

Time(Ti)

Du Exc.Ratemg/hr

Cumulativeamount

0 – 1 140 mg 140 1401 – 2 200 mg 200 3402 – 4 250 mg4 – 6 188 mg6 - 8 46 mg

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Urine Data

Time for the maximum rate of excretion is an index of the rate of bioavailability

The total cumulative amount of drug excreted in the uring is an index of the extent of bioavailability

BA = (D’u (oral)/D’u IV) x 100%

BR = (D’u test(oral)/D’u std(oral)) x 100%

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The following tetracycline plasma and urinary data are obtained following intravenous administration of 250 mg tetracycline to a 70 kg subject:

t(h) C,plasma (ug/ml)

t(h) X,urine (mg)

1.5 2.40 3 29.4

4 1.71 5 16.6

6 1.50 7 13.0

8 1.2 9 12.0

10 1.05 11 10.0

12 0.90 13 8.0

    73 62.0