Chloroform is a potentially toxic chemical

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October 18, 2020

Chloroform is a potentially toxic chemical

Toxicokinetics

PHCL 4760/5760

Homework Assignment #8

One-Compartment First-Order Absorption Homework

DUE: Thursday, October 4, 2018 at start of class

1. Chloroform is a potentially toxic chemical that is a common environmental contaminant due to

its frequent use in industrial processes and subsequent discharge in industrial waste.

Chloroform is also produced in chlorinated drinking water and in chlorinated swimming pools,

so that chloroform exposure occurs often through ingestion and dermal exposure. The following

chloroform data was collected in 250 g rats following bolus iv, oral (po), and intraperitoneal

(ip) administration.

10 mg/kg bolus iv

500 mg/kg po or ip

Time (hr) Civ (mg/L) Time (hr) Cpo (mg/L) Cip (mg/L)

0.083 2.679 0.00 0.00 0.00

0.50 1.988 0.25 7.87 12.73

1.0 1.359 0.50 11.19 18.98

2.0 0.730 1.0 15.07 24.32

3.0 0.401 2.0 11.64 20.02

3.0 7.32 12.02

4.0 4.63 7.27

6.0 1.79 2.53

Using this data, determine:

(a) k, C0, V, and AUC* for the bolus iv data

(b) k, ka, B1, and AUC* for the po data

(c) k, ka, B1, and AUC* for the ip data

(d) relative bioavailability for po vs ip, Fpo/Fip

(e) absolute po bioavailability, Fpo

(f) absolute ip bioavailability, Fip

*You may use the shortcut methods to calculate AUC if you desire.

Graduate Students (enrolled in PHCL 5760) should also answer (1g) and (1h):

(g) theoretical time for maximum level, tmax

(h) how does the theoretical tmax compare to the measured tmax?

2. Diethylene glycol (DEG) is used in many products, including glue, gelatin, tobacco, cheese,

gum drops, antifreeze, soaps, cosmetics, and ice cream. At high enough levels, DEG can cause

CNS depression, kidney damage, coma, and death. To evaluate DEG toxicokinetics, the

following measurements were made in 250 g rats following oral administration of 18.2 µCi of 14C-DEG:

Time

(min)

Plasma DEG Levels

(µCi/L)

0 0.0

2 9.7

4 19.2

7 25.3

9 37.8

12 39.6

14 45.8

17 48.8

20 52.0

25 56.4

30 59.2

35 60.1

40 61.1

45 62.1

50 62.8

60 63.1

70 62.1

80 60.1

90 57.3

100 55.5

110 53.7

120 52.2

150 48.0

180 45.0

240 39.0

Note that a µCi is a measure of the amount of radioactivity, and hence in this case is a measure of the

amount of 14C-DEG.

Given that the oral bioavailability of DEG is essentially 100%, estimate the following from this data:

(a) elimination rate constant, k

(b) elimination half-life, t1/2,elim

(c) absorption rate constant, ka

(d) absorption half-life, t1/2,abs

(e) volume of distribution, V

(f) clearance, CL

Graduate Students (enrolled in PHCL 5760) should also answer (2g) and (2h):

(g) theoretical time for maximum level, tmax (h) how does the theoretical tmax compare to the measured tmax?

3. Chemists at a food additive company have developed a new artificial sweetener that shows no

signs of causing cancer or other serious illnesses in rodents. Based on preliminary human tests,

however, it can cause drowsiness at plasma levels above 30 mg/L. Measurements from these

preliminary tests indicate the following human toxicokinetic parameter values: t1/2,elim = 4.6hr,

t1/2,abs = 0.34hr, VD = 0.29 L/kg, Foral = 72%. Based on these parameters, estimate the following

for a 49 kg woman after she consumes 1.0 g of the new sweetener:

(a) Estimate the plasma concentration of the sweetener at 1hr, 6 hr, and 20hr after consumption.

(b) Estimate the time for maximum plasma concentration (tmax).

(c) Estimate the maximum plasma concentration (Cmax).

(d) Estimate the time at which the plasma level first rises above 25 mg/L. (Note this is a trial

and error problem where you must guess a time, plug it into the concentration equation, and

determine if it is close to 25 mg/L. Hint: based on part (a) it should be apparent that the

answer is less than 1hr.)

(e) Estimate the time at which the plasma level finally drops to 25 mg/L. (Note that this again

is a trial and error problem, as in part (d). Hint: based on (a) the answer should be between

1 and 6hr.)

(f) Estimate the total time that this woman’s plasma level is expected to be above the

drowsiness causing concentration of 25 mg/L.

 

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