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

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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
Naproxen a
99 b 5-6 99.7 ± 0.1 c 0.13 ± 0.02 e 0.16 ± 0.02 e 14 ± 1 T-IR: 2-4 f T-IR: 37 f
a RD, Aged, d b RD a RD, RA, i RD, RA, T-CR: 5 f T-CR: 94 f
LD Child Child
b RA, Alb i Aged, d Cirr, d i Aged, a Aged d S: 2.2 ± 2.1 f S: 55 ± 14 μg/mL f
Child
Child
a RA
a
Metabolically cleared by CYP2C9 (polymorphic) and CYP1A2. b Estimated bioavailability.
c
Saturable plasma protein binding yields apparent nonlinear elimination kinetics. d No change
in total CL, but a significant (50%) decrease in CL of unbound drug; it is thus suggested that
dosing rate be decreased. A second study in elderly patients found a decreased CL and
increased t 1/2
with no change in percent bound. e CL/F and V area
/F reported. f Following a single
Niacin a
— b 12 c — 14.6 ± 5.0 d — ~0.15-0.25 e ER: 4-5 f ER (1 g): 0.6 μg/mL f
a Food
ER (2 g): 15.5 μg/mL f
a
Niacin (nicotinic acid) is metabolized to nicotinamide, which in turn is converted to the coenzyme
NAD and other inactive metabolites. It also undergoes direct glycine conjugation to
nicotinuric acid. b The absolute bioavailability is not known. Niacin is well-absorbed but
undergoes first-pass metabolism. Absorption is improved when taken with a low-fat meal.
c
Recovery of unchanged drug after multiple oral dose administration. d CL calculated from C ss
(6.6 ± 2.4 μg/mL) during an IV infusion of niacin. Niacin metabolic CL appears to be saturable.
e Estimated from the terminal log-linear portion of a disappearance curve following the
Nifedipine a
250-mg dose of suspension (S) given orally to pediatric patients or a 250-mg immediaterelease
tablet (T-IR) or a 500-mg controlled-release tablet (T-CR) given to adults.
Reference: Wells TG, et al. Comparison of the pharmacokinetics of naproxen tablets and
suspension in children. J Clin Pharmacol, 1994, 34:30–33.
end of a 0.1-mg/kg/min IV infusion in two subjects. f Following a single 1-g or 2-g oral dose
of extended-release (ER) NIASPAN. Markedly disproportional increases in plasma concentrations
with increasing dose.
References: Ding RW, et al. Pharmacokinetics of nicotinic acid-salicylic acid interaction. Clin
Pharmacol Ther, 1989, 46:642–647. PDR58, 2004, p. 1797. Piepho RW. The pharmacokinetics
and pharmacodynamics of agents proven to raise high-density lipoprotein cholesterol. Am
J Cardiol, 2000, 86:35L–40L.
50 ± 13 ~0 96 ± 1 7.0 ± 1.8 0.78 ± 0.22 1.8 ± 0.4 b IR: 0.5 ± 0.2 c IR: 79 ± 44 ng/mL c
a LD, Aged b LD, RD b LD, Aged a LD, RD, a LD, RD, Aged ER: ~6 c ER: 35-49 ng/mL c
Aged
i RD i RD, Smk i Smk i Smk
a
Metabolically cleared by CYP3A; undergoes significant first-pass metabolism. b Longer
apparent t 1/2
after oral administration because of absorption limitation, particularly for
extended-release (ER) formulations. c Mean following a single 10-mg immediate-release (IR)
capsule given to healthy male adults or a range of steady-state concentrations following a
60-mg ER tablet given daily to healthy male adults. Levels of 47 ± 20 ng/mL were reported
to decrease diastolic pressure in hypertensive patients.
References: Glasser SP, et al. The efficacy and safety of once-daily nifedipine: The coat-core
formulation compared with the gastrointestinal therapeutic system formulation in patients with
mild-to-moderate diastolic hypertension. Nifedipine Study Group. Clin Ther, 1995, 17:12–29.
Renwick AG, et al. The pharmacokinetics of oral nifedipine—A population study. Br J Clin
Pharmacol, 1988, 25:701–708. Soons PA, et al. Intraindividual variability in nifedipine pharmacokinetics
and effects in healthy subjects. J Clin Pharmacol, 1992, 32:324–331.