ABSTRACT
We sought to determine whether gestational age affects the transplacental transfer
and metabolism of buprenorphine (BUP). Transfer of BUP (10 ng/mL) and its [3H]-isotope was determined across placentas of 30 to 34 weeks of gestation utilizing
the technique of dual perfusion of placental lobule. Concentration of the drug in
trophoblast tissue and in maternal and fetal circuits was determined by liquid scintillation
spectrometry. Microsomes prepared from placentas of 17 to 37 weeks of gestation were
divided into three groups: late second, early third, and late third trimesters. Antibodies
raised against human cytochrome P450 (CYP) isoforms were utilized to identify the
enzyme(s) catalyzing BUP biotransformation by preterm placental microsomes. The amount
of norbuprenorphine formed was determined by liquid chromatography-mass spectrometry
(LC-MS). BUP transfer across the placentas of 30 to 34 weeks of gestation was similar
to those at term. CYP19 antibodies caused 60% inhibition of BUP metabolism by microsomes
of late second and early third trimesters and 85% by microsomes of late third trimester.
The developmental changes occurring in human placenta between 30 weeks of gestation
through term do not affect the transfer of BUP across human placenta. CYP19 is the
major enzyme responsible for biotransformation of BUP beginning at 17 weeks of gestation
until term.
KEYWORDS
Buprenorphine - transplacental transfer - metabolism - preterm - pregnant addict
REFERENCES
- 1
Johnson R E, Jones H E, Fischer G.
Use of buprenorphine in pregnancy: patient management and effects on the neonate.
Drug Alcohol Depend.
2003;
70
(2 Suppl)
S87-S101
- 2
Jones H E, Johnson R E, Jasinski D R et al..
Buprenorphine versus methadone in the treatment of pregnant opioid-dependent patients:
effects on the neonatal abstinence syndrome.
Drug Alcohol Depend.
2005;
79
1-10
- 3
Nanovskaya T N, Deshmukh S, Brooks M, Ahmed M S.
Transplacental transfer and metabolism of buprenorphine.
J Pharmacol Exp Ther.
2002;
300
26-33
- 4
Nekhayeva I A, Nanovskaya T N, Deshmukh S V, Zharikova O L, Hankins G DV, Ahmed M S.
Bidirectional transfer of methadone across human placenta.
Biochem Pharmacol.
2005;
69
187-197
- 5
Pasanen M, Pelkonen O.
The expression and environmental regulation of P450 enzymes in human placenta.
Crit Rev Toxicol.
1994;
24
211-229
- 6
Deshmukh S V, Nanovskaya T N, Ahmed M S.
Aromatase is the major enzyme metabolizing buprenorphine in human placenta.
J Pharmacol Exp Ther.
2003;
306
1099-1105
- 7 Miller R K, Koszalka T R, Brent R L. The transport of molecules across placental
membranes. In: Poste G, Nicolson GL, eds. The Cell Surface in Animal Embryogenesis
and Development. Amsterdam, New York, Oxford: North-Holland Publishing Company; 1976:
145-223
- 8
Hakkola J, Pasanen M, Hukkanen J et al..
Expression of xenobiotic-metabolizing cytochrome P450 forms in human full-term placenta.
Biochem Pharmacol.
1996;
51
403-411
- 9
Hakkola J, Raunio H, Purkunen R et al..
Detection of cytochrome P450 gene expression in human placenta in first trimester
of pregnancy.
Biochem Pharmacol.
1996;
52
379-383
- 10
Kitawaki J, Yoshida N, Osawa Y.
An enzyme-linked immunosorbent assay for quantitation of aromatase cytochrome P-450.
Endocrinology.
1989;
124
1417-1423
- 11
Kitawaki J, Inoue S, Tamura T et al..
Increasing aromatase cytochrome P-450 level in human placenta during pregnancy: studied
by immunohistochemistry and enzyme-linked immunosorbent assay.
Endocrinology.
1992;
130
2751-2757
- 12
Miller R K, Wier P J, Maulik D, di Sant'Agnese P A.
Human placenta in vitro: characterization during 12 h of dual perfusion.
Contrib Gynecol Obstet.
1985;
13
77-84
- 13
Nanovskaya T N, Nekhayeva I A, Hankins G D, Ahmed M S.
Transfer of methadone across the dually perfused preterm human placental lobule.
Am J Obstet Gynecol.
2008;
198
126.e1-4
- 14
Walsh S L, Preston K L, Stitzer M L, Cone E J, Bigelow G E.
Clinical pharmacology of buprenorphine: ceiling effects at high doses.
Clin Pharmacol Ther.
1994;
55
569-580
- 15
Jagsch R, Gombas W, Schindler S D, Eder H, Moody D E, Fischer G.
Opioid plasma concentrations in methadone-and buprenorphine-maintained patients.
Addict Biol.
2005;
10
365-371
- 16
Hieronymus T L, Nanovskaya T N, Deshmukh S V, Vargas R, Hankins G DV, Ahmed M S.
Methadone metabolism by early gestational age placentas.
Am J Perinatol.
2006;
23
287-294
- 17
Konje J C, Kaufmann P, Bell S C, Taylor D J.
A longitudinal study of quantitative uterine blood flow with the use of color power
angiography in appropriate for gestational age pregnancies.
Am J Obstet Gynecol.
2001;
185
608-613
- 18
Bassily M, Ghabrial H, Smallwood R A, Morgan D J.
Determinants of placental drug transfer: studies in the isolated perfused human placenta.
J Pharm Sci.
1995;
84
1054-1060
- 19
Nanovskaya T, Nekhayeva I, Karunaratne N, Audus K, Hankins G D, Ahmed M S.
Role of P-glycoprotein in transplacental transfer of methadone.
Biochem Pharmacol.
2005;
69
1869-1878
- 20
Nekhayeva I A, Nanovskaya T N, Hankins G D, Ahmed M S.
Role of human placental efflux transporter P-glycoprotein in the transfer of buprenorphine,
levo-alpha-acetylmethadol, and paclitaxel.
Am J Perinatol.
2006;
23
423-430
- 21
Nishimura M, Yaguti H, Yoshitsugu H, Naito S, Satoh T.
Tissue distribution of mRNA expression of human cytochrome P450 isoforms assessed
by high-sensitivity real-time reverse transcription PCR.
Yakugaku Zasshi.
2003;
123
369-375
- 22
Bièche I, Narjoz C, Asselah T et al..
Reverse transcriptase-PCR quantification of mRNA levels from cytochrome (CYP)1, CYP2
and CYP3 families in 22 different human tissues.
Pharmacogenet Genomics.
2007;
17
731-742
- 23
Zharikova O L, Deshmukh S V, Kumar M et al..
The effect of opiates on the activity of human placental aromatase/CYP19.
Biochem Pharmacol.
2007;
73
279-286
- 24
Iribarne C, Picart D, Dréano Y, Bail J P, Berthou F.
Involvement of cytochrome P450 3A4 in N-dealkylation of buprenorphine in human liver
microsomes.
Life Sci.
1997;
60
1953-1964
- 25
Kobayashi K, Yamamoto T, Chiba K et al..
Human buprenorphine N-dealkylation is catalyzed by cytochrome P450 3A4.
Drug Metab Dispos.
1998;
26
818-821
- 26
Picard N, Cresteil T, Djebli N, Marquet P.
In vitro metabolism study of buprenorphine: evidence for new metabolic pathways.
Drug Metab Dispos.
2005;
33
689-695
- 27
Moody D E, Slawson M H, Strain E C, Laycock J D, Spanbauer A C, Foltz R L.
A liquid chromatographic-electrospray ionization-tandem mass spectrometric method
for determination of buprenorphine, its metabolite, norbuprenorphine, and a coformulant,
naloxone, that is suitable for in vivo and in vitro metabolism studies.
Anal Biochem.
2002;
306
31-39
Mahmoud S AhmedPh.D.
Professor, Department of Obstetrics & Gynecology, University of Texas Medical Branch
301 University of Texas Medical Branch, Galveston, TX 77555-0587
eMail: maahmed@utmb.edu
