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Molecular size and breastfeeding?
In one of our standard sources on pregnancy and breastfeeding is heparin
described as an example of a drug that isn't excreted in breast milk
because of its molecular size. Were does the molecular size theory come
from and does it apply to other drugs as well? (Recently I got a
question about streptokinase and breastfeeding. We didn't find any
useful data on streptokinase and breastfeeding and I wondered if the
same theory could apply to this substance.)
All suggestions are welcome!
Erik F.O. Pomp, DI-pharmacist
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Molecular size is limiting the absorption through membranes in
general. However, for each type of membrane (GI tract, BBB, placenta,
skin) there is a different cut-off value. Often the molecular weight
is used as molecular size descriptor. This need not to be the best
choice. The reason for a size limitation is the relationship between
membrane diffusion and size: the bigger the slower.
Han van de Waterbeemd
Pfizer Central Research
Dept. Drug Metabolism
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[A few replies - db]
X-Sender: pberens.aaa.obg.med.uth.tmc.edu
Date: Tue, 16 Jun 1998 11:15:50 -0500
To: PharmPK.at.pharm.cpb.uokhsc.edu
From: Pamela Berens
Subject: Molecular Weight & Breastmilk
Mime-Version: 1.0
Erik,
Interestingly, when I check on my references re: MW and breastmilk they
state that " protein medications (Heparin, Insulin) which have enormous
molecular weights, are virtually excluded from human breastmilk". They
make no mention to the specific molecular weight where this occurs and
provid no sitations to reference regarding their statement so I can not
direct you further.There are other properties such as the milk: plasma
ratio which are important. A book which you may find useful is Medications
and Mother's Milk by Thomas Hale. He may have further information for you
and I have found him to be very approachable with questions. He is
Associate Professor of Pharmacology and Associate Professor of Pediatrics
at Texas Tech in Amarillo, Texas. Hope this helps.
Pamela Berens M.D.
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Date: Tue, 16 Jun 1998 17:57:13
From: Janusz Byczkowski
To: PharmPK.at.pharm.cpb.uokhsc.edu
Subject: Re: PharmPK Molecular size and breastfeeding?
Mime-Version: 1.0
Erik F.O. Pomp, DI-pharmacist
^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^
ANSWER:
Well, with breast milk nothing is simple and easy (especially from
kinetic point of view). Please visit my Web site " Drugs and Toxic
Chemicals in Breast Milk":
http://members.aol.com/JanuszB/milkpage.htm
for more detailed input.
In summary:
Although chemicals with molecular weight greater than 200, in general,
have difficulty in crossing cell membranes, in the case of Heparin it is
its acidic character rather that molecular weight that prevents its
penetration to breast milk (heparin is ionized at physiological pH). Due to
unique mechanisms of breast milk production and secretion, some larger drug
molecules and even proteins may enter the alveolar cells by pinocytosis
(well documented in experimental animals):
first, some large molecule may attach itself to the surface of the cell
membrane; next, the membrane engulfs this large molecule and brings it
inside the cell by "pinching off" the engulfed portion of membrane;
consequently a portion of membrane with the large molecule trapped inside
may be attached to the cellular membrane on the other side of the cell and
finally secreted into the milk by "reverse pinocytosis".
Alternatively, some large molecules may enter directly into milk via
spaces between alveolar cells. Although the intercellular structures in
humans are very tight, some macromolecular complexes and even whole viruses
may penetrate from the capillary to the interstitial space and to
intercellular cleft and finally to milk.
For more specific information inspect these references:
Minamishima I, Ueda K, Minematsu T, Minamishima Y, Umemoto M, Take H,
Kuraya K. Role of breast milk in acquisition
of cytomegalovirus infection. Microbiol Immunol 1994;38(7):549-552.
Mahajan L, Wyllie R, Steffen R and Kay M. Mother-to-infant transmission of
hepatitis C virus and breast-feeding J. Pediatr.
1995, 127:670-671.
Lin HH, Kao JH, Chen PJ and Chen DS. Mother-to-infant transmission of
hepatitis C virus and breast-feeding - Reply J.
Pediatr. 1995, 127:671.
Black RF. Transmission of HIV-1 in the breast-feeding process. J Am Diet
Assoc 1996 Mar;96(3):267-274.
Van de Perre P, Lepage P, Homsy J, Dabis F. Mother-to-infant transmission
of human immunodeficiency virus by breast milk:
presumed innocent or presumed guilty? Clin Infect Dis 1992 Sep; 15(3):502-507.
Nieburg P, Hu DJ, Moses S and Nagelkerke N. Contribution of breastfeeding
to the reported variation in rates of
mother-to-child HIV transmission AIDS 1995, 9:396-397.
Palasanthiran P, Ziegler JB, Stewart GJ, Stuckey M, Armstrong JA, Cooper
DA, Penny R,
Gold J. Breast-feeding during primary maternal human immunodeficiency virus
infection and risk of transmission from mother
to infant. J Infect Dis 1993 Feb;167(2):441-444.
Broadhead RL. Transmission of HIV-1 in breast milk. Trop Doct 1996
Jul;26(3):100-101.
About HIV virus see URLs:
http://qrd.tcp.com/qrd/aids/cdc/daily.summaries/1994/april/04.22.94
http://www.latrobe.edu.au/www/microbio/milk.html
http://www.hivpositive.com/f-NewsLine/f-US-News/us-98-01-01.html
http://webzone1.co.uk/www/cathus/wen7.htm
Frederick IB, White RJ, Braddock SW. Excretion of varicella-herpes zoster
virus in breast milk. Am J Obstet Gynecol 1986
May;154(5):1116-1117.
Olthof E, de Vries TW. [Breast feeding and oral anticoagulants]. [Article
in Dutch]
Tijdschr Kindergeneeskd 1993 Oct;61(5):175-177.
Golding J. Unnatural constituents of breast milk--medication, lifestyle,
pollutants, viruses. Early Hum Dev 1997 Oct 29;49
Suppl:S29-S43.
---
From: Stephen Duffull
To: "'PharmPK.at.pharm.cpb.uokhsc.edu'"
Subject: RE: PharmPK Molecular size and breastfeeding?
Date: Wed, 17 Jun 1998 09:06:35 +0100
MIME-Version: 1.0
Dear Erik
A comment about drugs and breast feeding.
There seems to be two aspects to your question. The first regarding
molecular weight, and the second regarding the diffusion of drugs into
human milk.
1) In the first instance it is the square root of molecular weight that is
usually related to diffusion across membranes. For drugs diffusing into
human milk this is, however, relatively unimportant except for very large
molecules (eg heparin). For heparin et al it must also be considered that,
irrespective of the amount that does cross into milk (even if this is
negligible), they are not absorbed orally by the infant anyway (as long as
the infant has normal gut anatomy and is not premature).
2) A variety of models have been used in order to predict drug diffusion
into human milk. The main predictors are:
log P, pKa, and plasma protein binding. Protein binding is more important
for basic drugs and pKa for acidic drugs. A particularly useful reference
to drugs and human milk is provided by P Bennett (Elsevier pub.) and is now
in the 2nd edition.
I hope this helps.
Steve
=======================
Stephen Duffull
School of Pharmacy
University of Manchester
Ph +44 161 275 2355
Fax +44 161 275 2396
Email: sduffull.-a-.fs1.pa.man.ac.uk
---
Date: Wed, 17 Jun 1998 11:15:07 -0500
From: "Dr. Gamal Hussein"
Reply-To: GHussein-clinPharm.at.worldnet.att.net
MIME-Version: 1.0
To: PharmPK.-at-.pharm.cpb.uokhsc.edu
Subject: Re: PharmPK Molecular size and breastfeeding?
My fellow and I are working on this topic for a year now. It is one of
the least understood subject even so it is very significant one. One of
the best articles written , in my opinion, is by Benoit Baily and Shinya
Ito (Pediatric CLinics of North America 1997:44:1;41-54). All proposed
equations to predict plasma/milk ratio does not include molecular size,
this is assuming small size of most drugs. The determining factors
include pKa, fraction of drug that is protein bound, and octanol/water
partition coefficient. We evaluated over 1200 drugs and developed FG-LA,
the first clinical lassification of drugs used during pregnancy, the
classification describes many parameters including the drug excretion
into milk and documented adverse effects on infants and lactatating
mothers. Data was presented at 1998 LSHP Annual Meeting, it will also be
presented at the upcoming American Public Health Meeting (Nov. 1998,
Washington, DC.), it will be submitted for publication soon.
Gamal Hussein, Pharm.D. at http://www.ClinPharmInt.com/Hussein.htm
Associate Professor of Pharmacy
Northeast Louisiana University-Pharmacy School
Associate Professor of Neurology
Louisiana State University-Medical School
Clinical Coordinator of Clinical Pharmacy/Pharmacology Program
The Medical Center of Louisiana at New Orleans
http://www.ClinPharmInt.com/Orleans.htm
email=PYHussein.at.Alpha.NLU.edu
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Greetings, Erik!
The 6th edition of Koda-Kimble's Applied Therapeutics has an excellent
section regarding the principles of breast feeding and drug excretion.
The chapter cites Berglund et al. for its three principles dictating which
drugs are excreted in breast milk (Acta Obstet Gynecol Scand
1984;126(Suppl):11.
I hope this information proves useful.
With best regards,
Vince Pearson, Pharm.D., BCPS
Clinical Coordinator, Drug Information
The Johns Hopkins Hospital
Baltimore, Maryland USA
On Mon, 15 Jun 1998, Erik Fred Oscar Pomp wrote:
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A few replies - db]
Date: Wed, 17 Jun 1998 16:56:08 -0400 (EDT)
From: VINCENT EARL PEARSON
To: PharmPK.-a-.pharm.cpb.uokhsc.edu
cc: Multiple recipients of PharmPK - Sent by
Subject: Re: PharmPK Molecular size and breastfeeding?
MIME-Version: 1.0
Greetings, Erik!
The 6th edition of Koda-Kimble's Applied Therapeutics has an excellent
section regarding the principles of breast feeding and drug excretion.
The chapter cites Berglund et al. for its three principles dictating which
drugs are excreted in breast milk (Acta Obstet Gynecol Scand
1984;126(Suppl):11.
I hope this information proves useful.
With best regards,
Vince Pearson, Pharm.D., BCPS
Clinical Coordinator, Drug Information
The Johns Hopkins Hospital
Baltimore, Maryland USA
---
From: Erik Fred Oscar Pomp
To: PharmPK.at.pharm.cpb.uokhsc.edu
Subject: SV: PharmPK Molecular Weight & Breastmilk
Date: Thu, 18 Jun 1998 10:17:23 +0200
MIME-Version: 1.0
Thank you all for the valuable information, just fantastic.
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