Learning objectives

• • • •

To know what data is available from pharmacokinetic studies in man and how to handle it To know how to calculate the basic pharmacokinetic parameters of clearance, t(half); volume of distribution, bioavailability; Kel To understand the implications of these parameters for satisfactory therapy and the construction of suitable dosage regimens for patients To know how knowledge of pharmacokinetic parameters can be exploited in drug design and formulation development.

Pharmacokinetics

Study of ADME on a quantitative basis In man study blood, urine, faeces, expired air.

Measure urine volume & concentration of drug conc in urine x vol per min = RENAL plasma concentration CLEARANCE If neither secreted nor reabsorbed then clearance clearance of inulin = 120 ml/min = If completely cleared by secretion then clearance = clearance of p-hippuric acid = renal blood flow = 700 ml/min

Plasma concentration 14

t

o

-tK el 12

t

o

el

10 8 6 4

t

o

el .

t 2.303

y = c m x 2 0 0 5 10 TIME (hours) 15 20

Plasma concentration 60 50 i.v. route

Bioavailability

(AUC) o / (AUC) iv 40 oral route 30 20 10 0 0 2 4 Time (hours) 6 8

1.6

1.1

=1.5; antilog 1.5 = 31.6

t

o

el .

t 2.303

0.6

0.1

-0.4

0 -0.9

5 log plasma concentration 10 TIME (hours) 15 20

Pharmacokinetic parameters

Volume of distribution V = DOSE / Co

Plasma clearance Cl = Kel .V

plasma half-life (t 1/2 ) directly from graph or t 1/2 = 0.693 / Kel

Bioavailability (AUC)x / (AUC)iv

Multiple dosing

On multiple dosing plasma concentration will rise and fall with each dose andwill increase until administration = elimination ie. steady state is reached.

At steady state hourly dose rate (D=dose; T=interval between doses in hours) D/T = clearance x plasma conc or steady state conc = D/(T x clearance)

At each dose the level will oscillate through D/V

plasma conc 6 5 4 3 2 1 0 0 5 toxic effective Cumulation and use of loading doses 10 15 Time 20 25