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The developmental disposition of diphenhydramine (DPHM) and its metabolites, diphenylmethoxyacetic acid (DPMA) and DPHM-N-oxide (DPHMNO), was investigated in postnatal lambs. Lambs received a DPHM intravenous (iv) bolus 15 days (Group A; n = 5) or 2 months (Group B; n = 6) after birth. Total body clearance of DPHM in postnatal lambs (Group A = 138.7 +/- 80.5 mL/min/kg; Group B = 165.7 +/- 51.3 mL/min/kg) was similar to the nonplacental clearance values (i.e., the component of fetal total body clearance that is not due to elimination via the placenta) estimated for fetal lamb (116.3 +/- 49. 6 mL/min/kg), and significantly greater than estimates in adult sheep (38.5 +/- 12.3 mL/min/kg). In addition, Group A DPHM renal clearance (CL(r), >1.80 +/- 1.24 mL/min/kg) was similar to that of the fetus (2.06 +/- 0.24 mL/min/kg), and significantly greater than that for Group B (0.26 +/- 0.17 mL/min/kg) and the adult (0.012 +/- 0.005 mL/min/kg). In contrast, similar to the fetal situation, postnatal DPMA CL(r) (Group A = 0.02 +/- 0.02 mL/min/kg; Group B = 0.05 +/- 0.01 mL/min/kg) was significantly less than adult values (0. 53 +/- 0.19 mL/min/kg). Because DPMA is not sequentially metabolized in sheep, the lower CL(r) in postnatal lambs results in longer apparent elimination half-lives of this metabolite (Group A = 90.4 +/- 32.2 h; Group B = 13.13 +/- 11.0 h) compared with that in the adult (2.9 +/- 1.6 h). No age-related difference in DPHMNO CL(R) was observed. Alterations in the CL(r) of DPHM and DPMA are likely related to differences in the rate of development of mechanisms (i.e. , tubular secretion and reabsorption and glomerular filtration rate) involved in the urinary drug excretion of organic acids and bases.

The objective of this study was to identify the important factors that determine plasma concentrations of diphenhydramine (DPHM) in the mother and the fetus after maternal as well as fetal steady-state drug administration. Inter-relationships were evaluated between maternal and fetal placental and nonplacental clearances, plasma protein binding, and steady-state plasma concentrations of DPHM among data obtained from 18 pregnant sheep during late gestation. The major determinant of plasma DPHM concentrations in the mother after maternal as well as fetal administration appears to be maternal plasma protein binding and maternal nonplacental clearance. In contrast, the major determinant of fetal plasma DPHM concentrations after maternal drug administration was the extent of fetal first-pass hepatic drug uptake from the umbilical vein. However, after fetal drug administration, the fetal plasma concentrations were related to the extent of fetal plasma protein binding and fetal placental and nonplacental clearances. The index of fetal-to-maternal placental drug transfer after fetal drug administration (steady-state maternal-to-fetal plasma concentration ratio) was related to steady-state fetal plasma unbound fraction and fetal placental and nonplacental clearance. However, this index was not related to the magnitude of the factors operating on the maternal side of the placenta such as maternal plasma protein binding and maternal nonplacental clearance. This might indicate a lack of complete equilibration of the unbound drug concentrations on the two sides of the placenta at the exchange site.

The placental and nonplacental clearances of metoclopramide were studied in nine chronically instrumented, near-term pregnant sheep using a two-compartment open model. Metoclopramide was administered to the ewe and fetus on separate occasions as an initial iv bolus loading dose followed by a constant-rate infusion, with steady-state maternal and fetal plasma concentrations being obtained by 45 min. Following the maternal infusions, metoclopramide reached average steady-state concentrations of 50.0 +/- 20.2 ng/mL in the ewe and 27.1 +/- 8.6 ng/mL in the fetus, with a mean fetal-to-maternal concentration ratio of 0.57 +/- 0.14. The ability of the fetus to eliminate metoclopramide by nonplacental routes appears to be responsible for this ratio being less than unity, rather than differential protein binding and ion-trapping effects. Mean steady-state concentrations were 13.8 +/- 4.5 and 253.7 +/- 92.1 ng/mL in the ewe and fetus, respectively, after fetal drug administration. Metoclopramide was bound significantly less to fetal (39.5 +/- 8.9%) than to maternal (49.5 +/- 7.9%) plasma proteins, with values similar to that reported for humans (approximately 40%). Clearance of metoclopramide across the placenta from the fetus to the ewe (6.2 +/- 2.4 L/h/kg) was significantly greater than that in the reverse direction (4.3 +/- 1.3 L/h/kg) and accounted for approximately 80% of total fetal drug elimination. This may be explained by the higher percentage of fetal cardiac output to the placenta and the flow-limited transfer of this compound.(ABSTRACT TRUNCATED AT 250 WORDS)

Studies were conducted to characterize the pharmacokinetics of diphenhydramine in nonpregnant ewes after iv administration of 25-, 50-, 100-, and 200-mg doses of diphenhydramine hydrochloride on a crossover basis. Plasma drug concentration versus time data exhibited multiexponential characteristics. The initial distribution half-life increased from 5 to 9 min and the elimination half-life from 34 to 68 min as the dose was increased. There was also an increase in the volume of distribution (from 3 to 6 L/kg) with increasing dose. The elimination half-life and the volume of distribution after a 200-mg dose were significantly greater than after a 25-mg dose. There was, however, a linear increase in AUC0 infinity as dose was increased. The average total body clearance (approximately 5 L/h/kg) remained unchanged regardless of dose. The free fraction of diphenhydramine determined by equilibrium dialysis averaged 0.229 +/- 0.080, and the extent of drug binding to plasma protein was independent of the drug concentrations encountered (30-780 ng/mL) in the nonpregnant sheep in vivo. Concentration-independent binding of the drug was also confirmed by in vitro binding studies over the drug concentration range 10-2000 ng/mL. Therefore, it appears that changes in the volume of distribution are likely to be a result of changes in tissue uptake or binding of the drug as a function of dose.

Pharmacokinetic studies of the histamine H1-receptor antagonist diphenhydramine were conducted in eight chronically instrumented pregnant sheep at 126-138 days of gestation. Diphenhydramine was administered by simultaneous intravenous bolus injection and infusion to steady state given 48 h apart, to the ewe and the fetus on separate occasions. Average steady-state drug concentration in plasma after maternal infusion was 212.1 +/- 67.8 ng/mL in the mother and 36.3 +/- 14.4 ng/mL in the fetus, resulting in a fetal-to-maternal concentration ratio of 0.19 +/- 0.10. Following fetal infusions, maternal and fetal steady-state drug concentrations were 31.1 +/- 11.6 and 447.6 +/- 185.2 ng/mL, respectively. The free fraction of diphenhydramine determined in the fetus (0.277 +/- 0.087) was significantly greater than that in the mother (0.141 +/- 0.079). Transplacental and nonplacental clearances were calculated at steady state according to a general two-compartment open model, with drug elimination occurring from both compartments. The total fetal clearance (472.7 +/- 215.7 mL/min) was relatively small compared with the total maternal clearance (3426.1 +/- 905.8 mL/min). The transplacental clearance from fetus to mother (264.4 +/- 138.7 mL/min) was approximately threefold higher than that from mother to fetus (82.4 +/- 40.5 mL/min). Maternal nonplacental clearance (3343.8 +/- 890.7 mL/min) accounted for 97.8 +/- 1.1% of the maternal total clearance, whereas fetal nonplacental clearance (208.4 +/- 80.4 mL/min) accounted for 45.1 +/- 4.7% of the fetal total clearance. It is concluded that in the fetus both the transplacental and nonplacental pathways are important for drug elimination.

The pharmacokinetics of metoclopramide was studied in chronically instrumented pregnant and nonpregnant sheep. Metoclopramide was administered to the ewe by intravenous bolus injections (on a crossover basis) of 10, 20, and 40 mg, with an additional 80‐mg dose to the nonpregnant animals. Transfer of the drug to the fetus was rapid with significant concentrations in fetal plasma 1 min after maternal dosing. The ratio of fetal‐to‐maternal area under the plasma concentration–time curves averaged 0.74, indicating significant fetal exposure to the drug. Maternal metoclopramide administration resulted in minimal fetal effects, with no change in arterial pressure, heart rate, or arterial pH or Pco2, and only a small (∼ 1.8 mm Hg) transient decline in Po2. Plasma concentrations in maternal and fetal plasma in most animals were best described by a biexponential equation with rapid distribution and elimination phases. The terminal elimination half‐lives in maternal and fetal plasma averaged 71.3 and 86.8 min, respectively, with fetal half‐life being significantly longer. The number of fetuses present had no consistent effects on either maternal or fetal pharmacokinetic parameters. Total body clearance and volume of distribution averaged 3.5 L/h/kg and 5.8 L/kg, respectively, in the pregnant ewe, and 4.5 L/h/kg and 6.9 L/kg, respectively, in the nonpregnant animals. The terminal elimination half-life in the nonpregnant ewes averaged 67.5 min. Pharmacokinetic parameters were compared in the pregnant and nonpregnant ewes at the 10-, 20-, and 40-mg doses, and no significant differences were observed in the distribution or elimination rate constants, elimination half-life, or volume of distribution. Total body clearance in the nonpregnant animals, however, was 22% higher than that calculated in the pregnant animals. Metoclopramide was observed to follow linear or dose-independent kinetics in both the pregnant and nonpregnant ewe over the 4–8-fold dose range studied.

To study the placental transfer and pharmacokinetics of the H1 receptor blocker, diphenhydramine [2-(diphenylmethoxy)-N,N-dimethylethylamine], 100 mg of the drug was administered to four pregnant sheep (122-129 d gestation) by intravenous injection through catheters chronically implanted in the ewe and fetus. Rapid placental transfer occurred, with peak fetal plasma concentrations occurring within 5 min after injection. The fetal-maternal ratio of the area under the plasma concentration versus time curves averaged 0.85, indicating significant fetal exposure to the drug. The average apparent terminal elimination half-life in the ewe (52 min) was not significantly different from that obtained in the fetus (46 min). The maternal total body clearance was 3.6 L X h-1 X kg-1, and the volume of distribution at steady state was 3.2 L/kg. In summary, this study demonstrates rapid and extensive placental transfer of diphenhydramine after maternal drug administration. Since placental permeability to lipid-soluble compounds does not differ greatly in different species, it is likely that a similar situation exists in humans.