Human pharmacokinetics of dihydroergotamine administered by nasal spray.

OBJECTIVES: A nasal spray of dihydroergotamine was developed for the treatment of migraine headaches, and pharmacokinetic studies were scheduled to evaluate the bioavailability of dihydroergotamine by this new route of administration. METHODS: Nine studies were performed with dihydroergotamine administered by nasal spray to evaluate the bioavailability of the nasal route versus the intramuscular route, the linearity of the kinetics, the interindividual and intraindividual variations, and the influence of different factors. RESULTS: Nasally administered dihydroergotamine (1 mg) becomes rapidly available to the systemic circulation, with peak plasma levels of 1 ng/ml achieved in 0.9 hour. The relative bioavailability versus intramuscular route is 38.4%. Dihydroergotamine administered by the nasal route exhibits linear dose proportionality (1 to 4 mg). Intraindividual variations of bioavailability evaluated for a 1-year period were higher (29%) than those found for the intramuscular route (20%) but comparable to the oral route. Interindividual variations for bioavailability were greater (25% versus 14% by the intramuscular route) but comparable to the oral route. Caffeine contained in the nasal solution (1%) had no effect on the absorption. Vasomotor phenomena, which could also affect the nasal mucosa during a migraine headache, do not modify the bioavailability. The constriction of the nasal mucosa by fenoxazoline leads to a slight decrease (-15%) in the bioavailability. The presence of acute viral rhinitis did not result in any change in dihydroergotamine nasal absorption compared with the normal state of the nasal mucosa. From a pharmacokinetic point of view, nasally administered dihydroergotamine can be given, without risk of overdose, to patients receiving long-term oral dihydroergotamine medication. CONCLUSION: These results show the reliability and reproducibility of this route of dihydroergotamine administration adapted for the treatment of migraine headaches.

Guanfacine kinetics in patients with hypertension.

Guanfacine kinetics were studied in 19 patients with hypertension after single and repeated oral doses. The single-dose study was performed in two homogeneous groups who received 2 mg (n = 9) and 4 mg (n = 10). The plasma concentrations were fitted in a two-compartment open model with first-order absorption. After a lag time of 0.8 hr, the absorption occurred rapidly (t 1/2 congruent to 0.53 hr). The fast and slow elimination phases occurred with t 1/2s of 2 and 19 hr. At therapeutic levels the percent of drug in red blood cells (55%) was independent of total drug concentration. Peak plasma levels had small interindividual variations. Comparison of kinetic parameters and AUC at the two doses studied demonstrated that their bioavailability was equal and the kinetics were linear. In a multiple-dosing study, performed in the same subjects, the plasma levels at steady state were in good agreement with the predicted values (p less than 0.001) and proportional to daily dosage. A single method based on four blood samples collected after 24, 28, 32, and 36 hr allows a reasonable prediction of the effective steady-state plasma levels during chronic dosing with guanfacine.

Pindolol availability in hypertensive patients with normal and impaired renal function.

Intravenous and oral pharmacokinetics of pinlolol were studied in 18 hypertensive patients-9 with normal renal function and 9 with impaired renal function. Analysis of data showed that a linear two-compartment model was suitable to describe the pindolol kinetics. Compared with patients with normal renal function, patients with chronic renal failure exhibited: (1) unchanged transfer rate constants and distribution volumes and (2) decreased total body clearance with decreased renal clearance and unchanged nonrenal clearance. Analysis of oral data by the Loo-Riegelman method showed that the pindolol absorption kinetic was not first order. Compared with patients with normal renal function, patients with chronic renal failure exhibited decreased fraction of dose effectively absorbed and increased initial rate of absorption. The initial rate of absorption was inversely correlated with the creatinine clearance. The study disclosed evidence that absorption was modified in chronic renal failure.

Pharmacokinetics and hepatic extraction ratio of pindolol in hypertensive patients with normal and impaired renal function.

The intravenous and oral pharmacokinetics and the hepatic extraction ratio of pindolol were determined in 24 hypertensive patients with normal or impaired renal function. In patients with normal renal function, the total clearance was the sum of equal parts of the renal and nonrenal clearances. The nonrenal clearance was found to be equal to the hepatic clearance directly measured from the hepatic extraction ratio. Compared to patients with normal renal function, patients with chronic renal failure exhibited (i) unchanged K12 and K21 and nonrenal clearances, and (ii) significantly decreased values in half-life of the beta phase, Kel, and total renal clearance. The renal clearance was positively correlated (P less than 0.01) to the creatinine clearance. Bioavailability was significantly reduced (P less than 0.01) in the patients with renal failure. Assuming that the nonrenal clearance was equal to the hepatic clearance, the study provides evidence that, in patients with renal insufficiency, (i) no increased metabolism accompanies the decrease in renal function, and (ii) decreased availability is due to reduced absorption.

Determination of pindolol in biological fluids by electron-capture GLC.

An electron-capture GLC method was developed for measuring pindolol in human plasma and urine. The unchanged drug was extracted with benzene from alkalinized plasma or urine using propranolol as the internal standard. Both compounds subsequently were back-extracted into 0.1 M HCl and then into benzene. After evaporation of the organic phase, the compounds were derivatized with trifluoroacetylimidazole to form the trifluoroacetyl ester of pindolol and propranolol. These derivatives then were analyzed by electron-capture GLC. The method allowed the measurement of concentrations as low as 1 ng of pindolol/ml of plasma and was applied successfully to determinations of plasma levels in humans after oral administraton of a single 10-mg dose of pindolol.

Determination of guanfacine in biological fluids by electron-capture GLC.

A quantitative electron-capture GLC method with good sensitivity is described for the determination of guanfacine in human plasma and urine. By condensing its amidino group with hexafluoroacetylacetone, guanfacine is converted to a pyrimidino derivative with better GLC properties than the parent drug. This method allows the determination of guanfacine in plasma and urine at concentrations as low as 0.5 ng/ml and was applied successfully to measurement of plasma levels in humans after therapeutic dosing.

Loss of vision.

Assessment of the patient with vision loss includes measurement of visual acuity, examination of the pupil, a finger-counting confrontation field examination, and an ophthalmoscopic examination. Opticokinetic testing is useful when functional blindness is being considered. A scheme is presented to use these findings to arrive at the anatomic level of this dysfunction. A differential diagnosis can then be generated. Some specific disorders causing vision loss are presented by anatomic location.

[Pharmacokinetics: a contribution in clinical geriatric pharmacology?]. / La pharmacocinétique: un apport en pharmacologie clinique gériatrique?

Clinical pharmacology in elderly patients and its therapeutic implications come up against the difficulty to consider independently the factor age from the other factors, influencing the kinetics in this population. The knowledge of pharmacokinetics give essential informations for the development of new pharmaceutical forms, adjustment of dosage regimen and recommendations for drug intake in order to minimize the variations in bioavailability and to improve compliance. In regard of results, obtained in such studies, individualized treatment in function of age could possibly be considered. These different aspects are illustrated by recent studies on dihydroergotoxine, a geriatric drug for which improvements in therapy, based on new kinetic informations and the development of new galenical forms, can be expected. Though pharmacokinetics is a useful tool in clinical pharmacology in elderly patients, more informations of the influence of age on the physiology and biochemistry are needed to better explain the difference of response of this population to drug treatment.

Mathematical model for in vivo pharmacodynamics integrating fluctuation of the response: application to the prolactin suppressant effect of the dopaminomimetic drug DCN 203-922.

We propose a general pharmacokinetic-pharmacodynamic model that integrates the rhythmic fluctuation of hormone secretion for the description of the hormone-lowering effect of a drug. The mathematical model takes into account the variation in response observed after administration of a placebo and the drug. It is assumed that the change with time in the physiological response during the placebo period results from fluctuations in the concentration of hypothetical endogenous molecules. The mathematical formulation for predicting the response after drug intake is derived assuming competitive interaction of these "molecules" with the active species for binding to receptors. The suggested "fluctuation model" was implemented in order to describe the time course of the prolactin (PRL) plasma level after administration of two oral doses (2.5 and 5.0 mg) of the dopaminomimetic compound DCN 203-922 (DCN) to 9 healthy male subjects. Its performance was compared with that of conventional modeling approaches, in which the circadian changes after placebo are neglected and the hormone baseline is assumed to be constant. The new model provided a better description of the time course of PRL in most subjects. It was used for prediction of the amplitude and duration of the PRL suppressant effect after single and chronic administration of DCN at various dosage regimens as well as after changes in drug absorption.

[Pharmacokinetics and metabolism of cyclosporin; drug interactions]. / Pharmacocinétique et métabolisme de la cyclosporine; interactions médicamenteuses.

The pharmacokinetic properties of cyclosporine and mainly its absorption and hepatic elimination can vary in each patient in relation to the subject's individual characteristics (inter-subject variability), as well as in an individual patient during his treatment because of clinical episodes or drug interactions (intra-subject variabilities). Therefore, it appears compulsory to follow regularly cyclosporine blood levels or even to characterise each subject following a dose-test during the initiation of treatment, in order to adapt an individual posology aiming to minimise as far as possible the risk of nephrotoxicity.

Influence of digestive secretions and food on intestinal absorption of nicardipine.

The role of digestive absorption in the pharmacokinetics of nicardipine has been studied by the perfusion technique. Nicardipine (40 mg) was perfused in six healthy subjects at 5 ml/min for 2 h either in isotonic saline with (Experiment A) or without (B) an occlusive balloon isolating the test segment from digestive secretions, or in a nutrient solution (Experiment C). In Experiments A and B, 100% of nicardipine was absorbed from the jejunal lumen in a 25 cm test segment and in Experiment C it was slightly lower (94%). There was no relationship between the absorption of nicardipine and water movement or bile salt concentration in the jejunum. Nicardipine was already present in the first plasma sample taken after 15 min and the peak level was found at the end of the perfusion. The areas under the curves differed widely between subjects, because of interindividual variation in the first pass effect, but they were similar in Experiments A, B and C. The experimental data showed a good fit to a mode involving a two-phase absorption process. The first phase was associated with intestinal perfusion (zero order process) and the second with passage across the intestinal wall (1st order process). In three further healthy subjects, nicardipine in saline was perfused in the jejunum and then in the ileum on consecutive days. Mean plasma levels over time were similar. The study showed that absorption of nicardipine both from the jejunum and the ileum was complete and was especially rapid. The food-induced change in the kinetics of absorption from the jejunum was too small to affect the pharmacokinetic parameters of nicardipine.

The effect of food and clopamide on the absorption of pindolol in man.

Plasma levels and urinary excretion of pindolol were measured in each of two groups of eleven subjects in order to compare the absorption of the drug when administered alone in the fasting state, and either with food or Binaldix. The data were analyzed according to a one-compartment model with first order absorption. No significant differences in absorption of pindolol were obtained in each study. Food appeared to increase the speed of absorption of pindolol leading to a slightly earlier and higher maximum plasma concentration, but this observation appears to be of no clinical relevance.

Drug interactions of the components of Optalidon after oral administration.

An investigation involving seven successive was undertaken on several groups of 10 to 14 volunteers, in order to evaluate any drug interaction between the three active components of Optalidon, namely amidopyrine (A), butalbital (B), and caffeine (C). Each component was investigated after oral administration, alone and in combination either with one of the others (i.e. A+B, B+C, C+A) or with both of the others in Optalidon (A+B+C). The plasma concentration and urinary excretion were recorded for each component as a function of time. For amidopyrine, two metabolites, amino-4-antipyrine and acetamino-4-antipyrine, were also measured in the urine. Based on a pharmacokinetic model, the following conclusions can be drawn: a) There is no change in bioavailability due to the combination of the three components in Optalidon in respect to their single administration. Within each study, there is no significant difference between the elimination rate constants, areas under the plasma concentration/time curve and percentage excreted in urine for the three components administered alone or in any combination with the other components of Optalidon. b) Concerning the absorption half-life, there is no change for amidopyrine. Only caffeine and butalbital show a statistically significant interaction in respect to this parameter and, as a consequence, differences in the time and value of the maximal plasma concentration in Optalidon. However, these differences are scarcely of anyl clinical relevance.

Pharmacokinetic aspects of guanfacine withdrawal syndrome in a hypertensive patient with chronic renal failure.

The unusual observation of a withdrawal syndrome due to guanfacine in a hypertensive patient with chronic renal failure led to a study of the kinetics of the drug in this patient. The principal pharmacokinetic parameters of guanfacine were greatly altered, with extended biotransformation and a decrease in the half-life compared to the values observed in other cases of severe renal insufficiency. Associated treatment with phenobarbital had had a considerable effect, as shown by the results of a further kinetic study 2 months after withdrawal of the phenobarbital. The findings then were in good agreement with reference values which strongly suggests a consequence of the enzyme inducing effect of phenobarbital. Advice about the dosage regimen in such cases is given.

Simultaneous study of the pharmacokinetics of intravenous and oral nicardipine using a stable isotope.

The systemic elimination of nicardipine has been studied by an initial oral administration of nicardipine followed 1.25 h later by intravenous injection of the deuterium-labelled molecule (D3 nicardipine). To check that intravenous kinetics was not modified by the oral administration, an i.v. injection of unlabelled nicardipine (D0 nicardipine) was also given. The study was carried out in six healthy male volunteers, aged between 24 and 27 years, according to a Latin square cross-over design. Similar values were found for each kinetic parameter after i.v. administration regardless of whether it was administered alone by that route or with an oral dose. The plasma level-time curves of nicardipine were described by a three open compartment model. The total plasma clearance was about 800 ml/min, the volume of distribution was of the order of 1 l/kg and the half-life of beta-elimination ranged from 4 to 5 h. The elimination rate constant beta was independent of the route of administration.

Quantification of ketotifen and its metabolites in human plasma by gas chromatography mass spectrometry.

Gas chromatography mass spectrometry with selected ion monitoring has been used to develop a method for the quantification of ketotifen and its demethylated, 10-hydroxy and 10-hydroxy demethylated metabolites in human plasma. The minimum detectable concentrations for ketotifen and its demethylated metabolites were 50 pg ml-1 and 300 pg ml-1 for the 10-hydroxy metabolite. The methodology has been applied in studies of the kinetics of the drug in man, and plasma levels of the unchanged drugs and its metabolites in free and conjugated form are reported.