Qsar Analysis of Drug Excretion Into Human Breast Milk

Meskin, M. S.; Lien, Eric J.

doi:10.1111/j.1365-2710.1985.tb00924.x

Cited by 20 publications

(17 citation statements)

References 15 publications

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“…Individual differences and diurnal changes in any of these latter factors will therefore result in variations in the observed M/P. In vitro studies performed by Meskin & Lein (1985) have shown that the unionised/ionised ratio of basic drugs (such as metronidazole) is more important than lipophilicity in dictating the drug's MIP and thus variations in the pH of milk and plasma will be reflected in the concentrations detected in milk.…”

Section: Discussionmentioning

confidence: 99%

Metronidazole excretion in human milk and its effect on the suckling neonate.

Passmore

McElnay

Rainey

et al. 1988

Brit J Clinical Pharma

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1. Milk and plasma metronidazole and hydroxymetronidazole concentrations were measured in 12 breast‐feeding patients following multiple doses of metronidazole (400 mg three times daily). All patients received metronidazole in combination with other broad spectrum antibiotics. 2. Plasma concentrations of both parent drug and metabolite were measured in seven suckling infants. Thirty‐five infants were monitored for adverse reactions to maternal metronidazole therapy and two further groups of suckling infants, those whose mothers received either ampicillin alone or no drug therapy, were recruited as controls. 3. The mean milk to plasma ratio (M/P) was 0.9 for metronidazole and 0.76 for hydroxymetronidazole while the mean milk metronidazole concentrations (around Cmax) were 15.5 micrograms ml‐1. The mean milk hydroxymetronidazole concentration was 5.7 micrograms ml‐ 1. 4. Infant plasma metronidazole concentrations ranged from 1.27 micrograms ml‐1 to 2.41 micrograms ml‐1, and the corresponding hydroxymetronidazole concentrations from 1.1 to 2.4 micrograms ml‐1. 5. There were no significant increases in adverse effects in infants which could be attributable to maternal metronidazole therapy. 6. Metronidazole was excreted in milk at concentrations which caused no serious reactions in the infants studied. The drug may therefore be administered at doses of 400 mg three times daily to mothers wishing to breast‐feed their infants.

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Section: Discussionmentioning

confidence: 99%

Metronidazole excretion in human milk and its effect on the suckling neonate.

Passmore

McElnay

Rainey

et al. 1988

Brit J Clinical Pharma

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“…Milk contains a higher content of lipids; therefore, lipid-soluble drugs would be expected to have a greater tendency to remain in the lipid phase. However, the partition coefficient has been reported to have a negative correlation with the milk-plasma ratios (Meskin & Lien 1985). This observation is explained by the greater degree of protein binding associated with drugs having a higher partition coefficient value (i.e.…”

Section: Excretion Of Drugs In Breast Milkmentioning

confidence: 97%

The Pharmacokinetics of Antiarrhythmic Agents in Pregnancy and Lactation

Mitani

Steinberg

Lien

et al. 1987

Clinical Pharmacokinetics

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The pharmacokinetics of various drugs may be profoundly altered during different stages of pregnancy, parturition, and lactation. Gastrointestinal absorption or bioavailability of drugs may vary due to changes in gastric secretion and motility. Various haemodynamic changes such as an increase in cardiac output, blood volume, and renal plasma flow may affect drug disposition and elimination. The increase in blood volume and total body water which occurs during pregnancy can alter the volume of distribution for various drugs. Although exact quantifications are not easy, these changes in pharmacokinetic parameters should be considered when dosing antiarrhythmic agents in pregnant women. Plasma protein concentrations and drug binding capacity are altered in the mother and fetus as pregnancy advances. With highly protein bound drugs, these changes may be clinically significant, as the pharmacological efficacy and toxicity are presumed to be related to the concentration of free drug in both the mother and fetus. In some instances, the fetus may be susceptible to greater drug toxicity as free drug concentrations may be underestimated by measurement of total drug concentrations. Changes in maternal drug metabolism and metabolism by the fetoplacental unit also contribute to alterations in the pharmacokinetics of drugs. As the placenta contains many metabolising enzymes, biotransformation of drugs at this site could potentially convert a drug into an active metabolite, or prevent fetal exposure to a toxic drug. Placental transfer of drugs, leading to toxicity in the fetus, is a major concern in the pharmacological management of the pregnant patient. The passage of individual drugs will vary depending on their apparent volumes of distribution, degree of protein binding the rates of metabolic conversion and excretion within the placenta and fetus, the pH difference between the maternal and fetal fluids, and maternal haemodynamic changes. Drug properties such as lipid solubility, protein binding characteristics, and ionisation constant (pKa) also influence the placental passage of drugs. For weakly basic antiarrhythmic agents, the fetal drug concentration may potentially exceed the maternal plasma concentration when the fetal pH is lowered as in the case of fetal acidosis; this is due to 'ion trapping'. Additionally, higher free drug concentrations of these basic drugs may exist, due to decreased alpha 1-acid glycoprotein concentration and binding affinity in the fetus. Lignocaine (lidocaine) has been shown to enter fetal plasma rapidly with fetal-maternal concentration ratios in the range of 0.52 to 0.66.(ABSTRACT TRUNCATED AT 400 WORDS)

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“…ACCEPTED MANUSCRIPT 35 there is a need to explore new molecular descriptors. Several sets of new molecular descriptors and molecular representations have emerged in recent years [92][93][94].…”

Section: Accepted Manuscriptmentioning

confidence: 99%