DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

1918
APPENDIX II
DESIGN AND OPTIMIZATION OF DOSAGE REGIMENS: PHARMACOKINETIC DATA
Table AII–1
Pharmacokinetic Data (Continued)
BIOAVAILABILITY URINARY BOUND IN CLEARANCE VOL. DIST. HALF-LIFE PEAK TIME PEAK
(ORAL) (%) EXCRETION (%) PLASMA (%) (mL/min/kg) (L/kg) (hours) (hours) CONCENTRATION
Codeine a
50 ± 7 b Negligible 7 11 ± 2 c 2.6 ± 0.3 c 2.9 ± 0.7 C: 1.0 ± 0.5 d C: 149 ± 60 ng/mL d
a
Codeine is metabolized by CYP2D6 (polymorphic) to morphine. Analgesic effect is thought
to be due largely to derived morphine. b Oral/IM bioavailability reported. c CL/F and V area
/F
reported. d Data for codeine (C) and morphine (M) following a 60-mg oral codeine dose given
three times daily for 7 doses to healthy male adults.
Cyclobenzaprine a
M: 1.0 ± 0.4 d M: 3.8 ± 2.4 ng/mL d
IR: 55 (51-60) 1 93 9.8 ± 3.1 — e 18 (8-37) f IR: 3.9 ± 1.8 g IR: 26 ± 11 ng/mL g
ER: — b b Aged c a Aged c ER: 7.1 ± 1.6 h ER: 20 ± 6 ng/mL h
b LD d
a LD d
a
Cleared primarily by cytochrome P450-dependent metabolism; multiple isoforms involved,
including CYP3A4 and CYP1A2. Both immediate-release (IR) and extended-release (ER) products
available. b Similar systemic exposure from a single 30-mg ER dose and three 10-mg IR
doses. c For both IR and ER products, systemic exposure is increased in the elderly, compared to
young adults. d Study in patients with mild to moderate hepatic impairment. e No published value
available; V β
estimated from reported mean clearance and t 1/2
= 15.3 L/kg. f Apparent t 1/2
of ER
product: 32 ± 10 hours. g Following the 10-mg IR product given three times daily to steady state
in young adults. h Following a single dose of the 30-mg ER product in young adults.
Cyclophosphamide a
Reference: Quiding H, et al. Plasma concentrations of codeine and its metabolite, morphine,
after single and repeated oral administration. Eur J Clin Pharmacol, 1986, 30:673–677.
References: Darwish M, et al. A pharmacokinetic comparison of single doses of once-daily
cyclobenzaprine extended-release 15 mg and 30 mg: A randomized, double-blind, two-period
crossover study in healthy volunteers. Clin Ther, 2009, 31:108–114. Darwish M, et al. Singledose
pharmacokinetics of once-daily cyclobenzaprine extended release 30 mg versus cyclobenzaprine
immediate release 10 mg three times daily in healthy young adults: A randomized,
open-label, two-period crossover, single-centre study. Clin Drug Investig, 2008, 28:793–801.
Hucker HB, et al. Physiological disposition and metabolism of cyclobenzaprine in the rat, dog,
rhesus monkey, and man. Drug Metab Dispos, 1978, 6:659–672. Winchell GA, et al.
Cyclobenzaprine pharmacokinetics, including the effects of age, gender, and hepatic insufficiency.
J Clin Pharmacol, 2002, 42:61–69.
74 ± 22 6.5 ± 4.3 13 1.3 ± 0.5 0.78 ± 0.57 7.5 ± 4.0 — 121 ± 21 μM b
a Child i Child b Child
b LD
a LD
i RD
a
Cyclophosphamide is primarily activated by CYP2C9 to hydroxycyclophosphamide. The
metabolite is further converted to the active alkylating species, phosphoramide mustard (t 1/2
=
9 hours) and nornitrogen mustard (apparent t 1/2
= 3.3 hours). Kinetic parameters are for
cyclophosphamide. b Following a 600-mg/m 2 IV (bolus) dose given to breast cancer patients.
References: Grochow LB, et al. Clinical pharmacokinetics of cyclophosphamide. Clin
Pharmacokinet, 1979, 4:380–394. Moore MJ, et al. Variability in the pharmacokinetics of
cyclophosphamide, methotrexate and 5-fluorouracil in women receiving adjuvant treatment
for breast cancer. Cancer Chemother Pharmacol, 1994, 33:472–476.