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
Hydrochlorothiazide
71 ± 15 >95 58 ± 17 4.9 ± 1.1 a 0.83 ± 0.31 c 2.5 ± 0.2 d SD: 1.9 ± 0.5 e SD: 75 ± 17 ng/mL e
b RD, CHF, b Aged b Aged a RD, CHF, b MD: 2 e MD: 91 ± 0.2 ng/mL e
Aged
a
Renal CL reported, which should approximate total plasma CL. b Changes may reflect
decreased renal function. c V area
calculated from individual values of renal CL, terminal t 1/2
,
and fraction of drug excreted unchanged; 70-kg body weight assumed. d Longer terminal t 1/2
of
8 ± 2.8 hours has been reported with a corresponding increase in V area
to 2.8 L/kg. e Following
a single (SD) or multiple (MD) 12.5-mg oral dose of hydrochlorothiazide; MD given once
daily for 5 days to healthy adults.
Hydrocodone a
— EM: 10.2 ± 1.8 — EM: 11.1 ± 3.57 b — EM: 4.24 ± 0.99 b EM: 0.72 ± 0.46 c EM: 30 ± 9.4 ng/mL c
PM: 18.1 ± 4.5 PM: 6.54 ± 1.25 b PM: 6.16 ± 1.97 b PM: 0.93 ± 0.59 c PM: 27 ± 5.9 ng/mL c
a
Data from healthy male and female subjects. The metabolism of hydrocodone to hydromorphone
(more active) is catalyzed by CYP2D6. Subjects were phenotyped as extensive metabolizers
(EM) and poor metabolizers (PM). b CL/F and t 1/2
reported for oral dose. c Following a
Hydromorphone a
References: Beermann B, et al. Pharmacokinetics of hydrochlorothiazide in man. Eur J Clin
Pharmacol, 1977, 12:297–303. Jordo L, et al. Bioavailability and disposition of metoprolol and
hydrochlorothiazide combined in one tablet and of separate doses of hydrochlorothiazide. Br J Clin
Pharmacol, 1979, 7:563–567. O’Grady P, et al. Fosinopril/hydrochlorothiazide: Single dose and
steady-state pharmacokinetics and pharmacodynamics. Br J Clin Pharmacol, 1999, 48:375–381.
10-mg oral dose (syrup). Maximal hydromorphone concentrations are higher in EM than in
PM (5.2 versus 1.0 ng/mL).
Reference: Otton SV, et al. CYP2D6 phenotype determines the metabolic conversion of
hydrocodone to hydromorphone. Clin Pharmacol Ther, 1993, 54:463–472.
PO: 42 ± 23 6 7.1 14.6 ± 7.6 2.90 ± 1.31 b 2.4 ± 0.6 IV: — c IV: 242 ng/mL c
SC: ~80 PO: 1.1 ± 0.2 c PO: 11.8 ± 2.6
ng/mL c
a
Data from healthy male subjects. Extensively metabolized. The principal metabolite,
3-glucuronide, accumulates to much higher (27-fold) levels than the parent drug and may
contribute to some side effects (not antinociceptive). b V area
reported. c Following a single
2-mg IV (bolus, sample at 3 minutes) or 4-mg oral dose.
References: Hagen N, et al. Steady-state pharmacokinetics of hydromorphone and hydromorphone-3-glucuronide
in cancer patients after immediate and controlled-release hydromorphone.
J Clin Pharmacol, 1995, 35:37–44. Moulin DE, et al. Comparison of continuous subcutaneous
and intravenous hydromorphone infusions for management of cancer pain. Lancet,
1991, 337:465–468. Parab PV, et al. Pharmacokinetics of hydromorphone after intravenous,
peroral and rectal administration to human subjects. Biopharm Drug Dispos, 1988,
9:187–199.