Nitrendipine in human plasma and breast milk

Summary To assess the disposition of the dihydropyridine calcium antagonist, nitrendipine, in lactating mothers, we studied three breast-feeding women to determine simultaneous plasma and breast milk concentrations of nitrendipine and its inactive pyridine analog metabolite after both a single 10 mg oral dose and 5 days of continuous therapy (20 mg per day).Nitrendipine was excreted in breast milk at peak concentrations ranging from 4.3 to 6.5 ng/ml 1–2 h after acute dosing while its inactive pyridine metabolite ranged from 6.9 to 11.9 ng·ml^–1. After 5 days of dosing, C_max remained in the same range and the breast milk/whole plasma concentration ratio for nitrendipine was 0.2 to 0.5. On the fourth day of continuous dosing, average concentrations of nitrendipine from 24-h collections of the milk were 1.1 to 3.8 ng·ml^–1.Thus, nitrendipine and its metabolite are excreted in very low concentrations in human breast milk. Based on a maternal dose of 20 mg daily, a newborn infant would ingest an average of 1.7 µg of nitrendipine per day, or a relative dose of 0.095%.Presented in part at the 3rd Annual Meeting of the American Society of Hypertension, New York, N.Y., June 24, 1988     

The tolerability,pharmacokinetics and lack of effect on plasma cholesterol of 447C88, an AcylCoA:Cholesterol Acyl Transferase (ACAT) inhibitor with low bioavailability,in healthy volunteers

447C88 (N-Heptyl-N-(2,4 difluoro-4-6-(2(-4-(2,2 dimethylpropyl)phenyl)ethyl)phenyl)urea) is an inhibitor of human microsomal AcylCoA:Cholesterol acyltransferase (ACAT) with an IC₅₀ of 10.2 ng·ml^–1 (23 nM). It is poorly absorbed but 5 mg·kg^–1·day^–1 completely abolishes the rise in plasma cholesterol in cholesterol-fed rats.In this study, twelve healthy, male volunteers received single, oral doses of 25, 50, 100, 200, 400 and 800 mg of 447C88 (n+8) or placebo (n+4) with food in a double-blind study with at least a week between occasions. The 400 mg dose was repeated after an overnight fast. Subsequently, fourteen different volunteers received a single 200 mg dose of 447C88 (n+8) or placebo (n+6) with food and, a week later, the same dose twice daily for 10 days; all doses were given with food.All doses were well tolerated with no significant changes in vital signs, full blood counts or plasma biochemical profiles. Plasma concentrations of 447C88 were unquantifiable after the fasting dose and low after all other doses. Mean C_max and AUC were 1.8 ng·ml^–1 and 9.0 ng·ml^–1·h after 200 mg rising to 5.4 ng·ml^–1 and 23.8 ng·ml^–1·h respectively after 800 mg; t_1/2 was 1.3 to 5.2 h. After 10 days dosing, plasma 447C88 concentrations were higher in the evening than the morning probably due to administration of the evening dose with more food. There were no significant changes in plasma triglcerides or total, LDL- or HDL-cholesterol after dosing with 447C88.     

Pharmacokinetics of verapamil in patients with hypertension

Summary Twelve hypertensive patients (WHO Stage I-II) were given oral verapamil (Isoptin) b.d. or t.d.s. as long-term treatment. The pharmacokinetics of verapamil and norverapamil were studied both after single and b.d. and t.d.s. doses of verapamil 240, 360 or 480 mg daily adjusted according to the blood pressure response. The apparent oral clearance of verapamil was decreased after both the twice and thrice daily dosage regimens (1.38 and 1.841/min, respectively) as compared to the single dose (4.39 l/min). The plasma half-life of verapamil was increased from 3.34 h (single dose) to 4.65 h (b.i.d.). Decreased elimination of norverapamil was also found after multiple doses of verapamil, as shown by an increase in the adjusted AUC of norverapamil (adjusted to a verapamil dose of 80 mg), namely from 574.9 h·ng·ml^–1 (single dose) to 1172 h·ng·ml^–1 (b.d.) and to 841 h·ng·ml^–1 (t.d.s.). The plasma half-life of norverapamil increase from 5.68 h to 7.34 h during twice daily dosing. During thrice daily verapamil, no increase in plasma half-life was found either for verapamil or norverapamil, probably due to the relatively short sampling time (6 h). The plasma concentration of verapamil and the reduction in supine systolic and diastolic blood pressure were correlated. The mean decrease in supine systolic blood pressure was 5.8 mm Hg per 100 ng verapamil/ml plasma, and for diastolic pressure 2.9 mm Hg per 100 ng verapamil/ml plasma. The mean steadystate plasma concentrations of verapamil were similar after twice and thrice daily dosing regimens, which agrees with the clinical observation that blood pressure control in hypertensive patients is as good after verapamil b.d. and t.d.s.     

The pharmacokinetics of amiloride-hydrochlorothiazide combination in the young and elderly

Summary The pharmacokinetics of amiloride and hydrochlorothiazide were studied in 12 healthy young volunteers following a single dose of a fixed combination of amiloride and hydrochlorothiazide and in 11 elderly hypertensive patients at steady-state. Following modelling of the single dose data, simulated steady-state plasma concentrations for the 2 drugs were generated to examine the effect of age and/or hypertension on pharmacokinetics.The apparent systemic plasma clearance for both amiloride and hydrochlorothiazide was significantly reduced in the elderly when compared to the young (from 753 to 325 ml·min^–1, amiloride; and from 418 to 157 ml·min^–1, hydrochlorothiazide). The plasma concentrations at steady state for both drugs were greatly increased in the elderly patients (Amiloride: from 7 to 25 ng·ml^–1, C_ss,max; from 2 to 8 ng·ml^–1, C_ss,min; and from 4 to 14 ng·ml^–1, C_av; Hydrochlorothiazide: from 184 to 651 ng·ml^–1, C_ss,max; from 31 to 121 ng·ml^–1, C_ss,min; and from 89 to 273 ng·ml^–1, C_av).The decreased clearance of the diuretics in the elderly was believed due to deterioration of renal function, and there was a significant correlation between the plasma clearance of hydrochlorothiazide and creatinine clearance in both age groups (r=0.62, young;r=0.72, elderly).As a result of the pharmacokinetic findings caution may be indicated in the clinical dosage of the diuretics particularly when in fixed dose combination.     

Single-dose and steady-state pharmacokinetics of sabeluzole in senile dementia of Alzheimer type patients

Summary The single- and repeated-dose pharmacokinetics of sabeluzole have been determined in six elderly patients with [senile] dementia of the Alzheimer type.After a single oral dose of 10 mg sabeluzole, the peak plasma concentration was attained at 1 to 4 h; it averaged 42 ng·ml^–1. On repeated dosing (10 mg b. d.), steady-state was virtually attained after 3 days of treatment. Steadystate mean trough and peak plasma concentrations fluctuated between 53 and 94 ng·ml^–1. The mean terminal half-life after a single dose and at steady-state was of the order of 33 h.Sabeluzole was well tolerated and at the end of treatment, no systematic changes in blood haematology, biochemistry or urinalysis were seen.     

Single dose pharmacokinetics of proguanil and its metabolites in pregnancy

Summary Plasma and whole blood concentrations of proguanil, its active metabolite cycloguanil, and the inactive metabolite 4-chlorophenyl-biguanide, were measured by HPLC in 10 healthy Karen women in the last trimester of pregnancy, following a 200 mg single oral dose of proguanil. Four of these women were restudied 2 months after delivery.The pharmacokinetic properties of proguanil were similar during and after pregnancy. Median peak plasma concentrations of proguanil during pregnancy and following delivery were 212 and 215 ng·ml^–1, and occurred at 4.5 and 5 h, respectively. Mean plasma AUC values for proguanil during and following pregnancy were 94 and 98 ng·h·ml^–1·kg^–1, respectively. Corresponding whole blood AUC values were 361 and 396 ng·h·ml^–1·kg^–1. The mean elimination half lives and mean residence times of proguanil in plasma and whole blood were 12.3 and 19.6 h and 13.8 and 20.7 h respectively during pregnancy. Following pregnancy these values were 17.1 and 19.7 h for plasma and 19.7 h and 20.2 h for whole blood respectively.Mean peak plasma and whole blood concentrations of cycloguanil following pregnancy were 25 and 22 ng·ml^–1 respectively. During pregnancy peak cycloguanil concentrations in both plasma and whole blood were markedly lower, 13 and 12 ng ml^–1, respectively. Two pregnant women (neither of whom were restudied) were probably poor metabolisers of proguanil. The mean ratio of proguanil to cycloguanil plasma AUC was 16.7 in the third trimester of pregnancy and 7.8 following pregnancy, compared with less than 5 in previously reported studies. The concentrations of 4-chlorophenylbiguanide in both plasma and whole blood in pregnant subjects were also lower than those after pregnancy.These data show that blood concentrations of the active antimalarial metabolite cycloguanil are reduced in late pregnancy and that the currently recommended dose of proguanil could be inadequate for antimalarial prophylaxis in pregnant women.     

Pharmacokinetics of oral salbutamol controlled-release in Asian patients with asthma

Summary Using a double blind, double dummy crossover design, single dose and steady state pharmacokinetics of oral controlled release (SCR) salbutamol 4 mg and 8 mg tablets b. d. has been studied in 8 Asian patients.Plasma salbutamol was measured over 12 h. In 8 patients the single dose mean C_max was 4.2 ng·ml^–1 and 7.7 ng·ml^–1 after 4 and 8 mg, respectively. In 5 patients the steady state mean C_max, C_min and t_max were 8.1 ng·ml^–1 and 4.7 ng·ml^–1 and 6 h for the 4 mg tablets and 14.1 ng·ml^–1 and 7.1 ng·ml^–1 and 4 h for the 8 mg tablets.It is concluded that both doses of SCR show features of controlled release and that they produced a relatively constant plasma level of salbutamol in Asian patients.     

Pharmacokinetics of methadone and its primary metabolite in 20 opiate addicts

In a closed metabolic ward the pharmacokinetics of methadone and its primary metabolite (EDDP) were studied in 20 long-term opiate addicts. After administration of the daily oral dose of methadone HCl (mean 60 mg, range 10–225 mg) blood samples were taken and analysed, using a newly developed high-performance liquid chromatography (HPLC) method. The steady-state plasma concentrations of the 20 subjects varied from 65–630 ng·ml^–1 and from 5 to 55 ng·ml^–1, whereas the peak concentrations were 124–1255 ng·ml^–1 and 10 – 301 ng·ml^–1 for methadone and EDDP, respectively. The calculated ratios between the area under the curve (AUC_{(0–24 h)}) for methadone and the AUC_{(0–24 h)} for EDDP varied from 5.9 to 44.6, indicating interindividual differences in metabolic activity. In 19 out of 20 subjects the pharmacokinetics of methadone are best described using a two-compartment model. The mean body clearance was 1.64 ml·min^–1·kg^–1, whereas the mean elimination rate constant () and plasma half-life (t _1/2) were 0.026·h^–1 (range 0.013–0.053·h^–1) and 31.2 h (range 13–53 h), respectively. Differences of gender were also found. A poor correlation was found between the methadone dose and the steady-state level. A much better correlation was found between the normalized steady-state level and the body clearance.     

Total and free steady-state plasma levels and pharmacokinetics of nifedipine in patients with terminal renal failure

Summary The total and free steady-state plasma levels of nifedipine in patients with renal failure have been compared with those in subjects with normal renal function. Studies were done after administration of nifedipine 10 mg t.d.s. p.o. for 5 days, after i.v. infusion of 4·4 mg, and after a single 10 mg oral dose.The systemic clearance of nifedipine after a single i.v.-dose was higher in subjects with renal insufficiency (854 ml/min) than in those with normal renal function (468 ml/min). After the single oral dose the AUC (6100 ng·min·ml^–1) and maximum plasma concentration (75.0 ng·ml^–1) were lower than in subjects with normal renal function (19300 ng·ml^–1; 122 ng·ml^–1). The plasma protein binding of nifedipine averaged 95.5% in normal subjects and 94.8% in patients with renal failure.Although free and total steady-state plasma levels of nifedipine tended to be somewhat lower than normal in renal failure, the changes in pharmacokinetics and decreased protein binding of nifedipine did not result in a significantly different steady-state plasma level of the drug. The blood pressure response to a given plasma nifedipine level appeared to be enhanced in renal failure.     

Pharmacokinetics and pharmacodynamics of thiazinamium in asthmatic patients

Summary The pharmacokinetics and pharmacodynamics of thiazinamium (Multergan) were studied after intravenous and intramuscular administration to 7 males with chronic reversible airways obstruction.Disposition after i.v. administration was described by a clearance of 0.54 l·min^–1, central compartment volume of 14.8 l, distribution rate constant 0.092 min^–1, and an elimination rate constant of 0.0044 min^–1. The corresponding estimates after i.m. administration were 0.324 l·min^–1, 34.1 l, 0.035 min^–1, and 0.0018 min^–1. The bronchodilator response (expressed as % predicted FEV1) after i.v. administration was characterized by maximum increase in FEV1 of 33.9%, with an EC₅₀ of 12.8 ng·ml^–1 and an equilibration half-time of 11 min. Corresponding parameter estimates after i.m. administration were 32.2%, 18.8 ng·ml^–1, and 9 min.Anticholinergic activity, measured by the change in heart rate after i.v. administration, showed maximum increase of 76 beats·min^–1, with an EC₅₀ of 176 ng·ml^–1 and an equilibration half-time of 1.3 min. After i.m. administration the corresponding values were 120 beats·min^–1, 250 ng·ml^–1, and 3 min.The optimal plasma concentration of thiazinamium was about 100 ng·ml^–1, which should give a near maximal bronchodilator response (over 80% of predicted normal) and a heart rate of about 100 beats·min^–1.     

Plasma concentrations and haemodynamic effects of nimodipine in patients resuscitated after cardiac arrest

Summary As the pharmacokinetics of a drug may be altered in haemodynamically compromised patients, the plasma concentrations and haemodynamic effects of the calcium entry blocker nimodipine have been examined in patients resuscitated after out-of-hospital cardiac arrest.In 7 patients nimodipine was infused at increasing rates up to 30 µg·kg^–1·h^–1. The plasma concentrations increased with increasing dose; at the highest dose a mean steady-state plasma concentration of 22.1 ng·ml^–1 was obtained, and the mean plasma clearance was 1.4 l·kg^–1·h^–1. There were no marked changes in mean arterial blood pressure or heart rate.In 9 other patients nimodipine was given as a bolus infusion of 10 µg·kg^–1 over 3 min, followed by a continuous infusion of 30 µg·kg^–1·h^–1. A mean steady-state plasma concentration of 17.6 ng·ml^–1 was obtained and the mean plasma clearance was 1.9 l·kg^–1·h^–1. Heart rate did not change significantly, but the mean arterial blood pressure fell.The data indicate that in patients resuscitated after cardiac arrest, the pharmacokinetics of nimodipine are not markedly different from patients with other conditions, e.g. subarachnoid haemorrhage. However, if a loading dose is given to obtain a steady-state concentration sooner, there will be a fall in arterial blood pressure.     

Predictive performance of population pharmacokinetic parameters of tianeptine as applied to plasma concentrations from a post-marketing study

Summary The predictive ability of population pharmacokinetic parameters of tianeptine, obtained from a mixed effect analysis of pre-marketing pharmacokinetic studies, was evaluated using tianeptine plasma concentrations obtained during a large multi-center post-marketing surveillance study.The mean prediction error was 7.8 ng·ml^–1 and the root mean square prediction error was 52.1 ng/ml when initial estimates of population pharmacokinetic parameters were used to predict drug concentrations in one half of the post-marketing data. When the population parameters were revised to reflect the data collected in the first half of the post-marketing study, the mean prediction error was reduced to –3.2 ng·ml^–1 and the root mean square prediction error was reduced to 29.5 ng·ml^–1.These results suggest that population pharmacokinetic parameters obtained from pre-marketing data may not accurately predict drug concentrations in patients receiving the drug in the post-marketing setting. Once the population parameters are updated to reflect data from the post-marketing period, the predictive ability of the database increases, but substantial variability in the prediction error remains.     

The absolute systemic availability of a new oral formulation of co-dergocrine in healthy subjects

Summary We have studied the absolute systemic availability (f) of an oral formulation (Hydergin spezial = Hydergine FAS^R 4 mg per tablet) of codergocrine by three different methods.Twelve healthy volunteers received single doses of 0.9 mg co-dergocrine intravenously and 8.0 mg orally in a randomized crossover design. The pharmacological effect of co-dergocrine was monitored as a reduction in plasma prolactin.Maximal plasma concentrations of co-dergocrine after oral dosing ranged between 0.181 and 1.307 ng·ml^–1. Maximal urinary excretion ranged between 4.7 and 9.9 µg·h^–1 and between 0.3 and 2.3 µg·h^–1 after intravenous and oral doses respectively. Clearance was measured as 90±22 l·h^–1 and the absolute systemic availability (f) as 2.25±0.65% by using the areas under the plasma concentration-time curves extrapolated to infinity. Calculation of f by comparing areas up to 32 h or the fractions of the dose excreted in urine led to identical results.The intravenous and oral doses produced similar pharmacological effects (reduction of plasma prolactin concentrations) despite the small value of f.     

Pharmacokinetics and dialysability of isradipine in chronic haemodialysis patients

Summary The pharmacokinetics of isradipine, a calcium-channel blocker, have been studied in eight patients on chronic haemodialysis. A single oral dose of 5 mg was administered on both a non-haemodialysis and a haemodialysis day and the plasma concentrations of isradipine were analyzed.The mean c_max, t_max, AUC, and t_1/2 in plasma on the non-haemodialysis day were 5.2 ng·ml^–1, 1.4 h, 23.8 ng·h·ml^–1, and 3.1 h, respectively. The dialysis clearance of isradipine was negligible (5.0 ml·min^–1).The t_1/2 values during haemodialysis were not significantly different from those observed during the same period post dose on the non-haemodialysis day. The study demonstrates that supplemental doses of isradipine are not necessary in these patients since isradipine is not significantly removed by haemodialysis.     

A double-blind placebo controlled dose response study of noberastine on histamine induced weal and flare

Summary The antihistaminic effects of 7 days treatment with each of three doses of noberastine (10, 20 and 30 mg) were compared to placebo in 12 healthy male volunteers. The antihistaminic activity was assessed from the inhibition of weal and flare formation after intradermal histamine injections. For both weal and flare there was a highly significant effect of treatment with each of the three doses of noberastine, compared to placebo. The 30 mg daily dose produced the maximum inhibition of weal and flare. The daily mean values for the assessment of sedation by visual analogue scales at 09.00 h, 15.00 h and 21.00 h showed no significant treatment, or order, effect for any of the three doses of noberastine compared to placebo. The mean steady-state plasma concentrations of noberastine were significantly higher with increasing daily doses of noberastine (trough concentrations: 1.0, 1.6 and 2.2 ng·ml^–1; peak concentrations: 3.5, 13.4 and 20.9 ng·ml^–1 for 10, 20 and 30 mg daily dose, respectively). The percentage weal inhibition correlated (r=0.77) with steady-state noberastine plasma trough levels. The percentage flare inhibition showed a weaker correlation (r=0.35) with steady-state noberastine plasma trough levels.     

Interaction of talinolol and sulfasalazine in the human gastrointestinal tract

Summary The absorption of talinolol (TA) 50 mg was investigated without and together with the co-administration of sulfasalazine (SASP) 4 g in 11 healthy young volunteers, in order to clarify gastrointestinal transit of TA.Without SASP, the t_max of TA was 2.8 h, C_max was 112 ng·ml^–1 and the half life was 12 h; the AUC_o-t was 958 ng·ml^–1·h.In the case of concomitant administration of SASP, TA was found only in serum from 3 individuals, with a C_max of 23 ng·ml^–1 and a mean AUC_o-t of 84 ng·ml^–1·h. TA was not detectable in 5 subjects and it was at the limit of detection (2 ng·ml^–1) in 3 subjects. Pharmacokinetic analysis was not possible in any of those individuals.The reason for the interaction appears to be the adsorption of TA by SASP. An interval of 2–3 h should elapse between giving SASP and other drugs.     

Studies on hydralazine

Summary After oral administration of a single 50 mg dose of hydralazine (Apresoline^®), the serum half-life (T1/2) and bioavailability (AUC_0–) were assessed in 16 healthy volunteers. The half-life was 2.57±0.14 h (S.E.) in 10 slow acetylators of sulphadimidine, and 2.18±0.15 h in 6 fast acetylators (difference not statistically significant). AUC_0– was significantly higher in slow acetylators, at 1.04±0.10 µg·hour·ml^–1, compared to 0.66±0.12 µg·hour·ml^–1 in the fast acetylators (p<0.025). Treatment with Apresoline^® 25 mg tid produced minimum serum concentrations at steady-state of 57.3±7.3 ng·ml^–1 and 33.4±4.2 ng·ml^–1 in 8 slow and 5 fast acetylators, respectively (p<0.05). The corresponding maximum concentrations were 228.8±20.3 ng·ml^–1 and 147.6±15.0 ng·ml^–1 in slow and fast acetylators, respectively (p<0.025). First-pass metabolism of hydralazine could explain the difference in bioavailability of the drug between fast and slow acetylators, without any corresponding difference in the elimination rate of the drug in the post-distributive phase.     

Modulation of allergen-induced nasal symptoms and mediator release by treatment with N-acetyl-aspartyl-glutamate (ZY15106)

The aim of this study was to evaluate the effects of the new anti-allergic drug, N-acetyl-aspartyl-glutamate (ZY15106), on allergen-induced nasal symptoms and mediator release. Fifteen outpatients suffering from seasonal allergic rhinitis due to grass pollen were included in the study. A nasal antigen challenge followed by evaluation of symptoms was performed in basal conditions. Ten of the 15 patients underwent sequential nasal lavages in order to evaluate allergen-induced mediator release. The study was performed in winter, when the patients were symptom free, and was a randomized single-blind crossover trial of a 6 % solution of ZY15106 (daily dosage: 48 mg) versus placebo (lactose). The drug and the placebo were administered intranasally q.i.d. for 1 week, with a 2-week interval between the two treatments. Treatment with ZY15106, but not with placebo, caused a significant reduction in nasal obstruction in the first 30 min after challenge and at 60 min and itching in the first 10 min after challenge, but did not reduce sneezing and rhinorrhoea. Moreover, ZY15106 significantly reduced the histamine release in 5 min postchallenge lavage (4.5 ng·ml^–1 after placebo administration vs 2.5 ng·ml^–1, after treatment with ZY15106). A reduction in immunoreactive LTC₄ release in the 5 and 10 min post-challenge lavages was observed after ZY15106 administration (placebo vs active treatment: at 5 min 2.9 ng·ml^–1 vs 1.4 ng·ml^–1; at 10 min: 2.25 ng·ml^–1 vs 0.9 ng·ml^–1). These results indicate that 1-week treatment with ZY15106 can reduce antigen-induced nasal obstruction and itching, and mediator release in human nasal airways. The clinical activity of ZY15106 in the treatment of allergic rhinitis may be related to its ability to inhibit mediator release.     

Single dose and steady-state pharmacokinetics of 4 mg and 8 mg oral salbutamol controlled-release in patients with bronchial asthma

Summary Fifteen patients with asthma were given salbutamol controlled-release (SCR) 4 mg or 8 mg twice daily for seven days, in a randomised double-blind cross-over design. Plasma salbutamol levels were measured after the first and fifteenth doses for a 12 h period following drug ingestion.At steady-state the geometric mean values for C_max were 8.2 ng/ml for 4 mg, and 16.1 ng/ml for 8 mg. Median t_max values were 300 and 240 min respectively. The geometric mean AUC (0–12) were 4507 ng·min·ml^–1 and 8980 ng·min/ml. Peak to trough fluctuation ratios were 0.577 and 0.572.There were no significant differences between 4 mg or 8 mg formulations, for any of the parameters measured, after appropriate corrections for dose. The concentration-time profiles at steady-state showed little fluctuation in plasma salbutamol levels over the twelve hour dosing interval. These results show that 4 mg and 8 mg formulations of SCR provide smooth plasma profiles at steady-state with a twice daily dosing regime.Part of this paper has been presented in abstract form to the British Thoracic Society, Newcastle, July 1988     

Therapeutic monitoring of nalbuphine: transplacental transfer and estimated pharmacokinetics in the neonate

Nalbuphine, a mixed agonist-antagonist opiate, is commonly used as a systemic analgesic during labour. Recent reports of perinatal adverse effects prompted us to carry out therapeutic nalbuphine monitoring in obstetric analgesia. Because data on fetomaternal transfer are scarce and the pharmacokinetics of this drug in the neonate are largely unknown, we report data obtained from 28 parturients treated with nalbuphine either intramuscularly and/or intravenously during labour. Plasma nalbuphine levels were measured by high-performance liquid chromatography (HPLC) with electrochemical detection. At delivery, 30–150 min after maternal administration, nalbuphine concentrations ranged from 5.0 to 79.2 ng·ml^–1 in mother plasma samples and from 3.0 to 46.6 ng·ml^–1 in umbilical cord plasma samples. Nalbuphine concentrations were highly correlated to dose. The fetomaternal ratio was high: 0.74 and not correlated to the administered dose of nalbuphine. An estimated plasma half-life of 4.1 h was calculated from two determinations in the neonate based on the assumption of a monoexponential decay of nalbuphine concentrations. Apart from a flattening of the fetal heart rate tracing in 54% of the cases, only one neonate had a low Apgar score at birth. The apparent prolonged half-life of nalbuphine in the neonate indicates the usefulness of an intramuscular injection of naloxone to prevent recurrence of cardiorespiratory depression due to nalbuphine administration to the mother.