Drug distribution into human milk

The two key equations, each with three independent variables, are as follows  

Few measurements of and (milk/lipid) have been made, but these parameters can be predicted from /, p and log P.  

It is clear from equations (5.49) and (5.50) that there is a degree of empiricism about these equations which arises in their derivation from the fitting of data sets based on the independent variables. The ratio M /P can be obtained from the modified Henderson-Hasselbalch equation  

When additives, such as surfactants and cyclodextrins, do not achieve appropriate 

Amidon, S. G. Yalkowsky and S. Leung, Solubility of nonelectrolytes in polar solvents. 11. Solubility of aliphatic alcohols in water. /. Phann. Set., 63, 1858-66 (1974) 

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The drug is also distributed into human-milk [4, 5, 10]. In lactating women who received 3 doses every 12 h of 750 mg of ciprofloxacin, the concentration of the drug in milk that was obtained 2-4 h after a dose averaged 2.26-3.79 pg/mL. Concentrations in milk were higher than concomitant serum concentrations for up to 12 h after a dose [10]. The plasma half-life is about 3.5-4.5 h, and there is an evidence of modest accumulation [4]. 

Chlorpromazine is 92 to 97% bound to plasma proteins, principally albumin [5,20], It crosses the blood-brain barrier, and concentrations of the drug in the brain are higher than those in plasma [17], The relationship of plasma concentration to clinical response and toxicity has not been clearly established. Chlorpromazine and its metabolites cross the placenta and are distributed into milk [21]. About 10-12 metabolites of chlorpromazine in humans have been identified. In addition to hydroxylation at positions 3 and 7 of the phenothiazine nucleus, the N-dimethylaminopropyl side chain of chlorpromazine undergoes demethylation and is metabolized to an N-oxide or sulfoxide derivative. These metabolites may be excreted as their 0-glucouronides, with small amounts of ethereal sulfates of the mono- and dihydroxy derivatives. The major metabolites found in urine are the monoglucouronide of N-demethylchlorpromazine and 7-hydroxychlorpromazine [2]. Although the plasma half life of chlorpromazine itself has been reported to be few hours, the elimination of metabolites may be very prolonged [8, 22-24]. 

The human genome contains nearly 900 genes that encode transporters, of which over 300 are intracellular transporters [1] responsible for transporting a wide range of molecules across the membrane [2]. Further classification of these transporters into families such as the solute carrier dass (SLC) [3] and ATP binding cassette (ABC) family 4, 5] is possible. Transporters play a major role in clinical pharmacology as their adequate bioavailability determines the successful oral delivery of many therapeutics. Membrane transporter proteins are associated with drug absorption (uptake), tissue distribution (efflux and uptake), metabolism (hepatic efflux and uptake), and elimination (renal, biliary transporters, and breast milk efflux and uptake) [6, 7]. 

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