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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5480_Библиотеки_им_академика_М_И_Перельмана.pdf
Pharmacokinetics
209
immediately. Urine and faeces were collected for 48 hr and frozen until they were assayed. The second
phase of the study was performed after a lapse of 3–7 days.
Analytical Methods: The total radioactivity in urine was determined directly via a liquid scintil-
lation counter (Model 2425). The total radioactivity in the faeces was measured after homogeniza-
tion (Polytron Homogenizer) and combustion in an oxidizer (Model B306). The procainamide and
N-acetylprocainamide concentrations in plasma and urine were determined by a specifi c high perform-
ance liquid chromatographic method.
The plasma concentration time plate of procainamide and N-acetylprocainamide for each rat was
fi tted to mono- and bi-exponential equations, respectively, using non-linear least squares regression
analysis. The elimination of N-acetylprocainamide is described by a two-compartment open model.
Results and Discussion: After dosing with procainamide, 84% and 5% of the total administered
radioactivity were eliminated in urine and faeces, respectively. Forty-nine percent of the amount recov-
ered in urine was unchanged procainamide and 20% was N-acetylprocainamide. As much as 31% was
excreted in an unidentifi ed form. After dosing with N-acetylprocainamide, 90.5% and 3.2% of the total
administered radioactivity were eliminated in urine and faeces, respectively. Of the amount recorded in
urine, 80% of the dose was unchanged N-acetylprocainamide and the remainder was unidentifi ed. Only
traces of procainamide were found in the urine of three rats after N-acetylprocainamide administration.
The mean elimination half-life of the N-acetylated metabolite of procainamides was 2.22 hr. The
mean values for the biological half-life of procainamide and N-acetylprocainamide were 0.658 and
2.13 hr; showing that the latter was about three times the former value. There was little difference in
the values of the volume of distribution of either drug—4.60 and 3.28 L kg
−1
for procainamide and
N-acetylprocainamide, respectively. The renal clearance of procainamide was 1.92 L hr
−1
kg
−1
, twice as
large as that of N-acetylprocainamide, 0.880 L hr
−1
kg
−1
.
Summary: Procainamide (I) is metabolized partially to N-acetylprocainamide (II) in rats but is
excreted mainly unchanged (~ 50% of the dose) in the urine. A small portion (3%–5%) of the intrave-
nous dose of both drugs was eliminated in the faeces, indicating biliary secretion.
The investigation of comparative pharmacokinetics in rats showed that the biological half-life of II is
about three times longer than that of I in rats. The volume of distribution of these drugs is quite similar.
The renal clearance of I (1.92 L hr
−1
kg
−1
) is twice as large as that for II (0.919 L hr
−1
kg
−1
).
In summary, the elimination of I and II when given individually to rats can be described by one- and
two-compartment open models, respectively.
8.3. Antianginal Drugs
Nitroglycerine (McNiff et al., 1981)
51
&+
212
212
&+
212
&+
1,2,3-Propanetriol trinitrate
Brand Name: Nitroglyn
®
(Key Pharmaceuticals).
51
McNiff EF et al.: J. Pharm. Sci., 70: 1054–1058, 1981.
Essentials of Biopharmaceutics and Pharmacokinetics
210
Other Names: Glyceryl trinitrate, Glonoin, Trinitrin. Sublingual nitroglycerine has been used exten-
sively for the relief of acute attacks of angina pectoris. Recently, it was shown to be effective in patients
with congestive heart failure following myocardial infarction.
8.4. Pharmacokinetics of Nitroglycerin after Intravenous Infusion in Normal Subjects
8.4.1. Experimental Procedure
Clinical Protocol: Eight healthy, non-smoking male adult volunteers were used as subjects. Prior to this
study and at least one week before receiving the nitroglycerin infusion, each subject was pre-screened
for nitroglycerin hypersensitivity by sublingual administration of 0.15 mg doses of nitroglycerin (USP
tablets) at different times for a total dose of 0.6 mg. Subjects who did not show any adverse reactions or
nitrate hypersensitivity were included. Nitroglycerin solution was supplied in 10 mL ampules containing
5 mg of nitroglycerin in a buffered solution of 10% ethanol. To 100 mL of normal saline (0.9 %), 5 mL
of this solution was added in a glass intravenous container just before use.
Nitroglycerin solution was infused into a peripheral forearm vein through a Polyter Catheter (Angiocath)
at a fl ow rate of 0.764 mL min
−1
for 32 min. Disposable plastic syringes, previously determined not to cause
drug loss, were used to draw blood samples through a peripheral vein cannula in the arm not used for infu-
sion. The cannula was then fl ushed with heparin (100 U mL
−1
) in 0.9 % sodium chloride. Samples (5 mL)
were drawn at 0 ( just prior to infusion) and at various times. The plasma was transferred to silanized glass
culture tubes, immediately centrifuged, separated and then placed on ice for storage at –20°C.
Analytical protocol plasma samples were assayed in duplicate according to GLC procedure.
Results and Discussion: Plasma nitroglycerin kinetics is characterized by rapid disappearance and
an apparently large plasma clearance. The plasma half-life of nitroglycerin determined from this study
was 2.8 ± 0.9 min. This value indicates a result of both blood degradation and organ metabolism of
nitroglycerin, the latter most probably by the liver (Maier et al., 1981).
52
The apparent plasma clearance determined in this study ranged from 0.31 to 1.03 L min
−1
kg
−1
cor-
responding to values of total body clearance of 29.8–78.3 L min
−1
.
Substantial inter-subject variability in nitroglycerin kinetics was observed in this study. In certain
subjects (but not all), the plasma nitroglycerin concentrations approached apparent steady-state values.
By using the apparent clearance values obtained, an apparent volume of distribution of 3.3 ± 1.2 L kg
−1
can be estimated. Minor fl uctuations in nitroglycerin content in the non-plasma (tissue) compartment,
which may result from a host of internal and external stimuli, could cause dramatic fl uctuations in
plasma nitroglycerin concentrations.
The mean half-life value of ~2.8 min refl ects in vivo spontaneous blood degradation of nitroglycerin in
humans. This rapid degradation is due to spontaneous hydrolysis or enzymatic breakdown of nitroglycerin.
Summary: Eight normal subjects received a dose of ~0.6 mg IV of nitroglycerin at a rate of 18 mcg
min
−1
. Plasma concentrations of intact drug during and after the infusion were determined using a GLC-
method. Intra- and inter-subject variability in nitroglycerin plasma kinetics was substantial. Generally,
however, plasma nitroglycerin disposition was characterized by
1. a large apparent plasma clearance
(0.3 – 1 L min
−1
kg
−1
)
2. a large volume of distribution
(~ 3 L kg
−1
) and
3. a rapid plasma half-life (~ 3min).
52
Maier GA et al.: J. Pharm. Sci., 70: 1057, 1981.
Pharmacokinetics
211
In conclusion, nitroglycerin kinetics is characterized by apparent extensive tissue distribution and
rapid plasma clearance.
8.5. Antineoplastic Agents
Fluorocuracil (Philips et al., 1980)
53
+
1
)
1+
2
2
5-Fluro-2,4(1H, 3H)-pyrimidinedione
Brand Names: Efudex
®
(Hoffmann-La Roche); Adrucil
®
(Adria).
Fluorouracil is of palliative value in certain types of carcinoma, particularly of the breast and the gas-
trointestinal tract.
8.6. Pharmacokinetics of Oral and Intravenous Fluorouracil in Humans
8.6.1. Experimental Procedure
Clinical Protocol: The subjects were 11 female patients undergoing therapy for breast carcinoma and
postmastectomy. The subjects were ambulatory and were being treated under the conditions of a multi-
centre trial to examine the benefi ts of cyclic adjuvant chemotherapy in both node-positive and node-neg-
ative operable breast cancer. Node-positive patients received fl uorouracil by intravenous injection, while
node-negative patients were dosed orally. Since each subject received either oral or intravenous fl uorour-
acil, it was not possible to examine fl uorouracil kinetics after oral and intravenous doses in the same person.
Intravenous doses of 250 mg of fl uorouracil were administered in 5 mL of water for injection into a
forearm vein over 30 s. Oral doses of fl uorouracil were administered in 10 mL of water for injection fol-
lowed immediately by 90 mL of orange juice. No dietary restrictions were applied. Blood samples (10 mL)
were taken from a forearm vein in the arm, not used for drug administration in the intravenous study, and
were placed in heparinized tubes. Plasma was promptly separated and stored at –20°C until it was assayed.
Analytical Protocol: Fluorouracil was extracted from plasma using a high performance liquid chro-
matographic (HPLC) system. The solvent was 10
−2
M phosphate buffer (pH 5.5). Uridine was used as
the internal standard. The lower limit of detection was 0.1 mcg mL
−1
, and neither commonly occurring
undersides nor drugs other than fl uorouracil being taken by the subjects interfered with the chromato-
graphic peaks of fl uorouracil or uridine.
Results: Individual plasma levels of fl uorouracil were obtained from the intravenous and oral doses.
Following intravenous dosing, plasma fl uorouracil levels at the 5-min sampling varied from 6.4 to 29.5
mcg mL
−1
with a mean value of 13.4 mcg mL
−1
. Drug levels declined monoexponentially. The mean
half-life of fl uorouracil in plasma was 6.3 min, the mean distribution volume was 0.2 L kg
−1
, and the
plasma clearance was 1410 mL min
−1
.
Following oral dosing, peak plasma levels of fl uorouracil ranged from 4.4 to 14.3 mcg mL
−1
with a
mean value of 8.3 mcg mL
−1
. The mean half-life of drug elimination was 7.2 min, while the absorp-
tion half-life time was 3.4 min. This value indicates fast absorption of fl uorouracil under the conditions
employed in this study.
53
Philips TA et al.: J. Pharm. Sci., 69: 1428–1431, 1980.
Essentials of Biopharmaceutics and Pharmacokinetics
212
Discussion: The mean distribution volume for fl uorouracil of 0.2 L kg
−1
and the plasma clearance
of 1410 mL min
−1
are consistent with previously reported values of 0.35 L kg
−1
and 1441 mL min
−1
obtained in three patients (Garrett et al., 1977)
54
and of 0.25 L kg
−1
and 1265 mL min
−1
obtained in eight
patients (McMillan et al., 1978).
55
Cohen et al. (1974)
56
suggested that the nature of fl uorouracil absorption may not only depend on the
vehicle with which the drug is administered, but also be infl uenced by the degree of hepatic involve-
ment. Garrett et al. (1977) obtained prolonged plasma levels of fl uorouracil from plasma after oral and
intravenous doses to patients with relatively normal liver function.
The results obtained in the present study are consistent with the hypotheses (Cohen et al., 1974; Garrett
et al., 1977). Absorption of fl uorouracil from the oral doses to subjects who had no discernible hepatic
involvement was effi cient and rapid. Although the clinical protocol prevented intravenous and oral doses
being given to the same subjects, thus preventing direct comparisons within an individual, the plasma
data nevertheless indicate that the oral dose was approximately 28% available as unchanged drug.
Furthermore, the data obtained in this study indicate that circulating levels of oral fl uorouracil may
be as reproducible between individuals as those obtained from intravenous doses.
Summary: The pharmacokinetics of fl uorouracil was examined after single 250 mg intravenous
doses and 500 mg oral doses to female patients with breast cancer. In fi ve patients who received intrave-
nous fl uorouracil, the mean plasma level of unchanged drug was 13.4 mcg mL
−1
, the elimination half-life
was 6.3 min and the plasma clearance was 1410 mL min
−1
. In six patients who received oral fl uorouracil,
the mean peak value of unchanged drug in plasma was 8.3 mcg mL
−1
and the elimination half-life was
7.2 min. The overall bioavailability of oral fl uorouracil as unchanged drug was 28% and the variation in
plasma drug levels between individuals was similar following oral and intravenous doses.
8.7. Antibiotics
Piperacillin Sodium (Batra et al., 1983)
57
:
+
&
1
11
1
1
+
++
&+
&+
&22
±
Â1D
6
+
2
2
2
2
2
Sodium (2S, 5R, 6R)-6-[(R)-2-(4-ethyl-2,3-dioxo-1-1piperazinecarbamido)-2-phenylacetamido]–3,
3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate.
Brand Name: Pipracil
®
(American Cyanamid Co.)
Piperacillin is a novel semi-synthetic penicillin that possesses broad spectrum anti-bacterial activity
against gram-negative and gram-positive pathogenic bacteria, including anaerobes. In certain cases, a
54
Garrett ER et al.: J. Pharm. Sci., 66: 1422, 1977.
55
McMillan WE et al.: J. Pharm. Sci., 38: 3479, 1978.
56
Cohen JL et al.: Cancer Chemother. Rep., 58: 724, 1974.
57
Batra VK et al.: J. Pharm. Sci., 72: 894–898, 1983.
Pharmacokinetics
213
piperacillin and gentamicin combination would be preferred to obtain a synergistic effect. To evaluate
the toxicity of these two drugs when administered alone or in combination, a one-month study was
undertaken in dogs. Since aminoglycosides can interact with β-lactam antibiotics, the study was designed
to allow the serum concentrations to be analyzed pharmacokinetically.
8.8. Pharmacokinetics of Piperacillin and Gentamicin Following
Intravenous Administration to Dogs
8.8.1. Experimental Procedure
Clinical Protocol: Six groups of 18–20 month-old beagle dogs (two males and two females in each
group) were utilized for the study. The weight range was 9.4–12.3 kg for the males and 7.9–9.6 kg for
the females.
Drug solutions, made prior to each dose, were administered twice daily (~5 hr apart) over a 5 min
period with an infusion pump (Respond 2000) calibrated using the specifi c syringes, solutions and tub-
ing employed. Doses administered were adjusted to the body weight twice a week. The concentration
of piperacillin solution in sterile water for injection, expressed as free acid, was 250 mg mL
−1
. The gen-
tamicin solution was made in concentrations of 1 and 2 mg mL
−1
using sterile isotonic saline. For drugs
that received both drugs, the solutions of piperacillin and gentamicin were prepared independently and
mixed in the infusion fl ow during administration.
Serum samples were obtained from one dog per sex-group prior to infusion and at various times follow-
ing the commencement of the infusion during the fi rst (Phase 1) and last (Phase 2) weeks of dosing. Urine
samples were collected for two consecutive days from all dogs during the fi rst and last weeks of the study.
Analytical Protocol: Antibiotic concentrations were determined by the disk diffusion method.
The assays for piperacillin were performed with Sarcina lutea (ATCC 9341) (indicator organism) grown
on antibiotic Medium No. 1
5
to which 0.6 % sodium polyanethole sulphonate was added to inhibit
gentamicin activity. The limit of detection was 0.16 mcg mL
−1
.
The assays for gentamicin were performed with Bacillus subtilis (ATCC 6633) grown on mycin agar
to which 1,000 kinetic units of penicillinase were added per millilitre of medium to inactivate the pip-
eracillin. The limit of detection was 0.16 mcg mL
−1
.
Results and Discussion: Following administration of 500 mg kg
−1
of piperacillin alone, the mean
serum concentration at the end of the infusion in Phase I was 2,475 mcg mL
−1
; after 5 min, it declined
rapidly and biexponentially. In Phase 2, no detectable levels of piperacillin were present before the start
of the infusion. At the end of the infusion, the serum concentration was 4,200 mcg mL
−1
, a level higher
than that seen in Phase I. After 5 min, serum concentrations were about the same magnitude as observed
in Phase I. Simultaneous administration of gentamicin did not change the serum piperacillin levels to
any signifi cant extent.
The time course of both piperacillin and gentamicin in the dog serum could be described by a two-
compartment open model. The pharmacokinetic parameters, except the volume of distribution of the
central compartment (V
C
), of both the drugs in Phase 2 were not different from those in Phase I. Even
though V
C
dropped signifi cantly in Phase 2, no statistically signifi cant change was observed either in the
volume of distribution at steady state (V
d SS
) or the overall volume of distribution (V
d
). The reason for
the lower V
C
in the second phase is not known.
Since the two drugs were given in combination, it was considered of interest to compare the pharma-
cokinetics of the piperacillin with that of gentamicin. Based on the data from both phases, the half-life
of piperacillin was 24 min, the body and renal clearances were 49 and 22 mL min
−1
, respectively, and the
volume of distribution at steady state was 228 mL kg
−1
. The corresponding values for gentamicin were
Essentials of Biopharmaceutics and Pharmacokinetics
214
70 min, 33 and 19 mL min
−1
, and 314 mL kg
−1
, respectively. Compared with gentamicin, piperacillin had
a shorter half-life and a larger body clearance. There were no statistically signifi cant differences either in
the volume of distribution or in the renal clearance of the two drugs.
Summary: Piperacillin sodium was administered intravenously to dogs, alone or in combination
with gentamicin, twice a day (~5 hr apart) for 36–37 days. Neither there was any signifi cant affect of
gentamicin on the pharmacokinetics of piperacillin, nor the pharmacokinetics of gentamicin changed
signifi cantly when piperacillin was administered simultaneously. However, the urinary recovery of gen-
tamicin decreased signifi cantly when it was co-administered with piperacillin. The similarity of the
pharmacokinetic parameters of gentamicin administered alone or in combination with piperacillin
clearly indicates that the inter-action between piperacillin and gentamicin occurred after excretion, i.e.,
either in the urinary bladder or in the collection container.
Suggested Readings
Benet LZ et al. (Eds.). Pharmacokinetic Basis for Drug Treatment. New York: Raven, 1984.
Davies SS, Prichard BNC (Eds.). Biological Effects of Drugs in Relation to Their Plasma Concentration. Baltimore, MD:
University Park Press, 1973.
D’Argenio DZ (Ed.). Advanced Methods of Pharmacokinetic and Pharmacodynamic Systems Analysis. New York: Plenum
Press, 1991.
Gibaldi M, Perrier D. Pharmacokinetics, 2nd edn. New York: Dekker, 1982.
Pecile A, Rescigno A. Pharmacokinetics, Mathematical and Statistical Approaches to Metabolism and Distribution of Chemi-
cals and Drugs. New York: Plenum Press, 1988.
Reidenberg MM, Erill S (Eds.). Drug-Protein Binding, Esteve Foundation Symposium I. New York: Praeger Publ.,
1986.
Shargel L, Yu ABC. Applied Biopharmaceutics and Pharmacokinetics. Norwalk, CT: Appleton and Lange, 1993.
Welling P, Tse F. Pharmacokinetic, New York: Marcel Dekker, 1993.
SECTION 4
Clinical Pharmacokinetics
7KLVSDJHLQWHQWLRQDOO\OHIWEODQN
4
Clinical Pharmacokinetics
CHAPTER OUTLINE
1. Introduction
2. Dosage Regimens: Design, Modalities and
Implementation
3. Single Dose Bioequivalence Study: Design and
Relevant Statistics
4. Pharmacokinetic Drug Interaction: Signifi cance in
Combination Therapy
1. Introduction
Clinical pharmacokinetics refers to the ‘application of pharmacokinetics to the safe and effective thera-
peutic management of an individual patient’.
In a broader perspective, the clinical pharmacokinetics is solely concerned with the phenomenon of
applying the pharmacokinetic principles and pharmacodynamic aspects to aid in the correct and proper
‘dosage-regimens’ for the individual patients.
However, at this point in time, it would be quite necessary to have a clear concept of the following
two terminologies frequently encountered in the present context, namely:
∑ How the body reacts to the drug (i.e., pharmacokinetics): It usually relates to the study and
understanding of such critical factors that actually determine the time course of drug that appears
eventually within the human body, viz. absorption, distribution, metabolism and excretion (ADME).
Estimation—In most cases, the actual concentration of a drug substance in plasma shall provide
a crucial refl ection of those present in the tissues of the body. It also encompasses such typical sites
where the desired/undesired effects are duly elicited.
∑ How the drug reacts to the body (i.e., pharmacodynamics): It is normally concerned with
the ensuing time course of a drug substance inside a human body. Besides, it relates to the specifi c
study of establishing the relationship among the following vital aspects:
_ Drug concentration
_ Pharmacological activity profi le
_ Toxicological response.
Essentials of Biopharmaceutics and Pharmacokinetics
218
Figure 4.1 shows the integrated relationship of the clinical pharmacokinetics closely concerned with the
phenomenon of utilizing important aspects as
∑ pharmacokinetic principles and
∑ pharmacodynamic criteria,
in order to help in the most judicious selection of the appropriate drug dosage regimens meant for the
individual patients.
It has been established beyond any doubt that for several drug substances there exists a unique rela-
tionship between
∑ drug responses and
∑ plasma–drug concentration.
Importantly, the emergence of intra-and inter-individual variability in pharmacokinetics appears to be
immense value, when such drug substances in which the ensuing plasma concentrations
1
overlap with
those needed for desired clinical effect.
In addition, the observed ‘variability in pharmacokinetics’ may invariably come into play due to the
following factors:
∑ Genetic infl uence
∑ Disease conditions,
∑ Ageing phenomenon,
∑ Drug–drug interactions,
∑ Environmental factors (viz. industrial pollutants, cigarette smoking etc.).
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Figure 4.1 Diagrammatic representation of clinical pharmacokinetics in relation to phenomenon of using
pharmacokinetic principles and pharmacodynamic aspects to aid in the selection of a suitable drug dosage
regimens for individual patients.
1
Usually in conjunction with ‘toxic effects’.