pharmacokinetics in pregnancy
TRANSCRIPT
Ji-Young Park, MD
Dept. of Clinical Pharmacology & Toxicology
Anam Hospital, Korea University College of Medicine
* = Pharmacokinetics (약동학) + Pharmacodynamics (약력학)
Absorption (흡수)
Distribution (분포)
Metabolism (대사)
Excretion (소실)
Receptor at action site
second messengers
(ATP, GTP…)
clinical effect
(BP ….)
3
PK
PD
ADME Absorption – the process of getting drug into the body (not necessarily the systemic circ
ulation)
Distribution – the processes of distribution into and out of the tissues
Metabolism – the processes that change the drug to another molecule
Excretion – the processes that remove drug from the body
Collectively, these processes are referred to as ADME
Tx. failure
Toxicity
치료반응의 예측
Use of blood concentrations of drug in PK
study
5
작용부위(ACTION SITE)
“수용체(RCEPTOR)” bound free
유리약물(Free drug) 흡수(ABSORTPION) 소실(EXCRETION)
조직 (TISSUE RESERVOIR)
free bound
대사 (BIOTRANSFORMATION)
bound drug 대사물(metabolite)
SYSTEMIC CIRCULATION
Drug
Dose Concentration
in plasma
Concentration
at effect site Pharmacological
Effect
Analytical
method Hard to
measure
(invasive)
Hard to
measure
(outcome)
Surrogate
marker
7
Plasma Concentration (ng/mL) versus Time (h) PK parameters F (Bioavailability)
Cmax
Tmax
AUCall (AUClast), AUCinf
Clearance
Volume of distribution (Vd)
Half-life
Ke (Elimination Constant)
MRT (Mean Residence Time)
*Absorption Oral absorption and bioavailability
Elevation of progesterone
Reduced gastric emptying time
Reduced intestinal motility
Cmax의 감소와 Tmax의 증가 minimal effect on bioavailability
Increase in gastric pH
ionization of weak acid reduction in absorption of weak acid drugs
More critical problems: nausea and vomiting associated with pregnancy
* Distribution Expansion of intravascular (plasma volume) and extra vascular (breasts, uterus, peripheral edema) water content.
* 임산부의 1/3에서 edema를 경험 (ECF가 최대 8L까지 증가)
Total body water의 증가
hydrophilc drug에 대한 Vd의 증가 apparent dilution of drug concentrations
(compensation by changes in protein biding)
Volume of distribution plasma volume (임신 6-8주부터 증가 32-34주까지) (약 1.2-1.3 L 증가) non-pregnant women에 비해 40% 증가 cardiac output의 증가와 관련
Plasma albumin 농도 감소 dilutional effect of plasma volume
원인: albumin 합성의 감소 또는 clearance의 증가 Increased in drug effect by elevation of free forms
α1-acid glycoprotein; relatively unchanged during pregnancy
Protein binding의 감소: free form 증가
Increase in body fat (약 4kg 증가) lipophilc drug에 대한 Vd의 증가
임상적 의의는 거의 없음.
Partially compensated respiratory alkalosis: protein binding에 영향
Organ blood flow의 증가
uterus, kidney, skin, and mammary gland
with compensatory decrease in skeletal muscle blood flow
Hepatic blood blow는 영향이 거의 없음 (but lower as a percentage of cardiac output
* Metabolism 대체로 약물 대사능은 증가함
몇몇 hepatic cytochrome P450 enzyme induction
원인: estrogen/progesterone 약물대사의 증가
Cholinesterase activity: 임신시 감소
CYP2D6 activity: increased in pregnancy
* Nelfinavir & active metabolite (M8) Pharmacokinetics
Heeswiik et al. CPT 2004
pregnancy (open circles)
Post partum (solid circles)
In conclusion, there is an increased prevalence of
subtherapeutic plasma nelfinavir concentrations
during pregnancy. In addition, concentrations of
the active metabolite M8 are significantly reduced.
* Caffeine Clearance – CYP1A2
Aldridge A, et al. Semin Perinatol 1981;5:310-4.
0
10
20
30
40
50
60
70
80
90
0 10 20
WEEKS POSTPARTUM
0
10
20
30
40
50
60
70
80
90
10 15 20 25 30 35 40
WEEKS OF PREGNANCY
CL
EA
RA
NC
E (
mL
/kg
x h
r)
BIRTH
* Lamotrigine clearance in pregnancy
Tran TA, et al. Neurology 2002; 59: 251-55.
Phase II biotransformation by glucuronidation
Increased clearance in second and third trimesters ( > 65%)
May require dose adjustment
Rapid decrease in clearance in the first two weeks postpartum
* Elimination
Renal blood flow: 임신시 60%증가 (최대 2배까지 증가하기도)
Glomerular filtration rate: 임신시 50% 증가
Unchanged form으로 제거되는 약물 (e.g. penicillin, digoxin)의 배설증가
80
100
120
140
160
180
200
15-18 wks 25-28 wks 35-38 wks 8-12 wks
CL
EA
RA
NC
E (
mL
/min
)
PREGNANT POSTPARTUM
CLCr
sitting
CLCr 24°
CLINULIN sitting
Davison JM, Hytten FE. Br J Obstet Gynaecol Br Commonw 1974;81:588-95.
* Theophylline clearance during pregnancy and postpartum
0
0.2
0.4
0.6
0.8
1
1.2
24-36 wks 36-38 wks 6-8 wks > 6 mo
CL
EA
RA
NC
E (
mL
/min
x k
g) CLE
CLNR
CLR
PREGNANT POSTPARTUM
Frederiksen MC, et al. Clin Pharmacol Ther 1986;40:321-8.
* Placental transport
*Passive diffusion
*P-glycoprotein expressed on trophoblastic cells of placenta
*Active transport of P-gp substrates back to the mother
*Pore system
*Endocytosis
MPERIPHERAL
MCENTRAL
FETUS
DOSE
CL E
FETAL
EXCRETION
+
METABOLISM
Placenta
* P-gp deficient mdr1a and mdr1b (-/-) CF-1 mice
pronounced increase in fetal exposure to P-gp substrates
ABC (ATP-binding cassette) drug efflux transporter
syncytiotraophoblast
Schematic representation of the role of the major placental efflux drug transporters in
syncytiotrophoblast layer.
BCRP: Breast cancer-resistance protein; MRP: Multi-drug resistance-associated protein; P-gp: P-
glycoprotein
* ABCG2 (BCRP) transporter
Kobayashi et al. DMD 2005
Placental BCRP mRNA (left) and protein (right)
expression levels in various BCRP haplotypes
Western blot analysis of BCRP expression in
human placentas
* Effect of gestational age
*Toxic insult by xenobiotics greater danger to fetus in early
pregnancy
*BCRP protein ↑ but not mRNA level with advancing gestational age
* Effect of maternal age
* Effect of genetic polymorphism
* Effect of hormones
*Progesterone and estrogen↓
* leflunomide case
Mean plasma concentrations of A771726 after a single dose of 20 mg
leflunomide orally according to ABCG2 c.421C>A (a) and c.34G>A (b) genotypes
* Teratogens act with specificity
* Teratogens demonstrate a dose-response relationship
*PK aspect:
* drug level modulation: ADME
* role of transporter: modulation of transporter activity * inhibitor or inducer
* genetic problems.