A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Darvocet-N Pharmacology, Pharmacokinetics, Studies, Metabolism - Propoxyphene Napsylate and Acetaminophen
Darvocet-N Pharmacology, Pharmacokinetics, Studies, Metabolism - Propoxyphene Napsylate and Acetaminophen
CLINICAL PHARMACOLOGY
Propoxyphene is a centrally acting narcotic
analgesic agent. Equimolar
doses of propoxyphene hydrochloride
or napsylate provide similar plasma concentrations. Following administration
of 65, 130, or 195 mg of
propoxyphene hydrochloride, the bioavailability of propoxyphene
is equivalent to
that of 100, 200, or 300 mg
respectively of propoxyphene napsylate. Peak plasma concentrations
of propoxyphene are reached in 2 to 2 ½ hours. After a 100-mg
oral dose
of propoxyphene napsylate, peak plasma
levels of 0.05 to 0.1 mcg/ml are achieved. The napsylate salt
tends to be absorbed more slowly than the hydrochloride. At
or near therapeutic
doses, this absorption difference is small when compared with that
among subjects and among doses (for graphic illustration please
see manufacturer's original package insert).
Because of this several hundredfold difference in solubility, the
absorption rate of very large doses of the napsylate salt
is significantly lower than that of equimolar
doses of the hydrochloride.
Repeated doses of propoxyphene at 6-hour intervals lead
to increasing plasma concentrations with a plateau
after the ninth dose at
48 hours.
Propoxyphene is metabolized in the liver
to yield norpropoxyphene. Propoxyphene has a half-life
of 6 to 12 hours, whereas that of norpropoxyphene is 30 to 36 hours.
Norpropoxyphene has substantially less central-nervous-system-depressant
effect than propoxyphene but a greater local
anesthetic effect,
which is similar to that of amitriptyline and antiarrhythmic
agents, such as lidocaine and quinidine.
In animal studies in
which propoxyphene and norpropoxyphene were continuously infused
in large amounts, intracardiac
conduction time
(PR and QRS intervals) was prolonged. Any intracardiac
conduction delay
attributable to high concentrations of norpropoxyphene may be of
relatively long duration.
Propoxyphene is a mild narcotic
analgesic structurally
related to methadone. The potency of propoxyphene napsylate is from
two thirds to equal that of codeine.
Propoxyphene napsylate and acetaminophen
tablets provide the analgesic activity of propoxyphene napsylate
and the antipyretic-analgesic activity of acetaminophen.
The combination of propoxyphene and acetaminophen
produces greater analgesia than that produced by either propoxyphene
or acetaminophen
administered alone.
ANIMAL PHARMACOLOGY
Animal Toxicology: The acute
lethal doses of the hydrochloride
and napsylate salts of propoxyphene were determined in 4 species.
The results shown in TABLE 1 indicate that on a molar
basis the napsylate salt
is less toxic than the hydrochloride. This may be due to the relative
insolubility and retarded absorption
of propoxyphene napsylate.
| TABLE 1 Acute Oral Toxicity Of
Propoxyphene |
| |
LD50 (mg/kg) ±
SE |
| |
LD50 (mmol/kg) |
|
Species
|
Propoxyphene Hydrochloride |
Propoxyphene Napsylate |
| Mouse |
282 ±
39 |
915 ±
163 |
| |
0.75 |
1.62 |
| Rat |
230 ±
44 |
647 ±
95 |
| |
0.61 |
1.14 |
| Rabbit |
ca. 82 |
>183 |
| |
0.22 |
>0.32 |
| Dog |
ca. 100 |
>183 |
| |
0.27 |
>0.32 |
Some indication of
the relative insolubility and retarded absorption
of propoxyphene napsylate was obtained by measuring plasma
propoxyphene levels in 2 groups of 4 dogs following oral
administration
of equimolar doses
of the 2 salts. The peak plasma
concentration
observed with propoxyphene hydrochloride was much higher than that
obtained after administration
of the napsylate salt.
Although none of the animals in this experiment
died, 3 of the 4 dogs given propoxyphene hydrochloride
exhibited convulsive seizures
during the time interval
corresponding to the
peak plasma levels. The 4 animals
receiving the napsylate salt
were mildly ataxic but not acutely ill. (For graphic illustration please
see manufacturer's original package insert).
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