Adipose tissue distribution and chemical structure of basic lipophilic drugs: desipramine, N-acetyl desipramine, and haloperidol.

Single-dose intravenous injections of desipramine to rats resulted in a distribution pattern typical of basic lipophilic drugs, i.e., highest concentrations in lung and lowest in adipose tissue and plasma. In contrast, after N-acetyldesipramine, a non-basic analogue of desipramine with comparable lipophilicity, concentrations of this drug in adipose tissue were much higher than in lean tissue or plasma as a result of redistribution into the former and rapid disappearance from the latter tissue. N-Acetyldesipramine had much lower plasma and tissue half-lives than desipramine, but at the same time a much higher adipose/plasma concentration ratio and adipose storage index. Chronic administration of the basic lipophilic drug, haloperidol, to rats in their diet over 21 days resulted in a steady-state distribution pattern with highest concentrations in lung and lowest concentrations without accumulation in adipose tissue. This study provides additional evidence for the influence of basic groups on the distribution of lipophilic drugs. Thus, basic lipophilic drugs do not undergo redistribution into adipose tissues, possibly because of a competition by stronger binding to lean tissue as a result of lysosomotropism.

Kinetics of distribution and elimination of DDE in rats.

1. Rats were given single i.v. doses of 14C-DDE, and total drug (14C) and unchanged DDE (g.l.c.) were measured for up to 14 days in blood, tissues, and excreta. The 14C recoveries amounted to 90.0 +/- 10.8 (SD) % dose. 2. DDE underwent redistribution from blood to liver, muscle, skin and, ultimately, adipose tissue. The tissue/blood concentration ratios were 6 for liver and muscle, 35 for skin, 400 for adipose tissue. Concentrations in blood and lean tissues declined biphasically with beta-half-lives of 8-12 days. The half-lives for adipose tissue and total body burden were larger by one order of magnitude. However, due to the increase of adipose tissue mass with time, the amount of DDE stored therein remained constant at almost 60% dose. 3. Except for liver, no substantial metabolite concentrations in tissues were found. In particular, lipophilic metabolites were clearly absent. Thus, tissue kinetics and storage are controlled by unchanged DDE. 4. Of a given dose of DDE, 31% was excreted in the faeces as polar metabolites within 14 days, and 3-4% dose as DDE. Urinary excretion was negligible. The beta-half-life of faecal excretion was equal to the one in blood and lean tissues. It is concluded that excretion is limited by the slow formation of polar metabolites of DDE.

Kinetics of distribution and adipose tissue storage as a function of lipophilicity and chemical structure. I. Barbiturates.

Distribution kinetics of 5-ethyl-substituted oxy-, N-alkyl-, and thiobarbiturates covering a range of partition coefficients of octanol/water (log P 1.6 to 4.1) were determined in rats. Concentration-time curves for plasma, adipose tissue, liver, and muscle after single iv administration were obtained using HPLC analysis. Pharmacokinetic parameters were calculated for plasma and tissues. A physiological pharmacokinetic model allowed the simulation and prediction of adipose tissue kinetics based on blood and plasma kinetics, adipose tissue/plasma distribution coefficient, volume and perfusion rate of adipose tissue. Adipose tissue storage was quantified with the adipose storage index (ASI). Including data of barbiturates from the literature, the correlation between ASI and log P was poor except for oxybarbiturates not substituted in N1. Within comparable log P ranges, ASI values increased from oxy- to N-alkylated to thiobarbiturates. Thus, even within the chemical class of barbiturates log P is not a sufficient criterion for adipose tissue storage. Rather, adipose tissue storage is influenced by individual functional groups.

Efficacy of stiripentol in the intravenous pentylenetetrazol infusion seizure model in the rat.

The potential effectiveness of stiripentol, a new allylic alcohol anticonvulsant, against generalized epilepsy of the absence type was evaluated in the intravenous pentylenetetrazol (PTZ) infusion seizure model in the rat. The ability of stiripentol to elevate the threshold dose of PTZ in eliciting clonic seizure (i.e., ratio of the post-drug threshold dose to the baseline threshold dose) was measured. Dose-response studies were performed after acute intraperitoneal injection and subacute oral drug treatment. Concentrations of stiripentol in plasma and whole brain were determined. Significant elevation in PTZ threshold dose was observed at a single 300 mg/kg intraperitoneal dose of stiripentol or at plasma levels exceeding 35 micrograms/ml. Maximal anticonvulsant response (i.e., a dose ratio of 3) was reached with doses at or above 450 mg/kg (or plasma concentration greater than or equal to 120 micrograms/ml), along with the appearance of neurotoxicity. Subacute treatment consisted of 9 consecutive oral doses of stiripentol over a 3 day period, until steady-state plasma stiripentol concentration was attained. Response data were obtained at dosage levels of 150, 400 and 800 mg/kg with respective mean steady-state levels of 33.2 +/- 7.8, 61.4 +/- 20.7, and 116 +/- 14 micrograms/ml. Maximal anticonvulsant effect was not reached even at the highest dose of 800 mg/kg. Correlation of threshold dose ratio with plasma and brain stiripentol concentrations showed an approximate 40% loss in anticonvulsant potency during subacute treatment. However, the animals also became more resistant to drug-induced neurotoxicity; about 40% higher plasma or brain stiripentol concentrations had to be reached for a given degree of neurotoxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

Single-dose kinetics of tissue distribution, excretion and metabolism of amiodarone in rats.

In order to better understand the pharmacokinetic differences between acute and chronic regimens of the basic lipophilic antiarrhythmic, amiodarone (AM), a mass-balanced single-dose study ([14C]AM, 50 mg/kg, i.v.) was carried out until total elimination had been achieved (10 days). Total drug, AM and desethylamiodarone (DEA) were determined in plasma, eight tissues and excreta of rats with constant body weight. Three exponential terms were sufficient to describe the plasma concentration-time curve of unchanged AM with a long terminal half-life of 131 hr. An equally long terminal half-life of AM could also be observed in all tissues investigated. After 5 min, 42% of the radioactivity appeared in the liver, where it underwent redistribution to muscle, skin and, ultimately, adipose tissues. Whereas plasma and liver contained mainly unidentified metabolites and little DEA, unchanged AM predominated in all other tissues. According to the time-integrated parameters of distribution, AM has a potential to accumulate in adipose tissue under chronic administration. In contrast, DEA accumulation would be likely to occur in lean tissues, mainly in the lung. In 10 days, 94% of the injected radioactivity was excreted in feces and less than 2% in urine. Almost all of the excreted radioactivity consisted of unidentified metabolites, indicating that both AM and DEA are eliminated by metabolism.

Application of thermospray liquid chromatography-mass spectrometry to the simultaneous quantification of tracer concentrations of isotopically labelled carbamazepine epoxide and steady-state levels of carbamazepine and carbamazepine epoxide.

A thermospray high-performance liquid chromatography-mass spectrometry method for the separation and quantification of tracer concentrations of isotopically labelled carbamazepine epoxide ([15N, 13C]CBZE) in the presence of steady-state levels of the anticonvulsant carbamazepine (CBZ) and its epoxide metabolite (CBZE) has been developed. The technique does not require derivatization, demonstrates little or no thermal degradation of the analytes, provides increased specificity not available from conventional high-performance liquid chromatography, and has a detection limit of 500 pg for CBZE on-column. The method, incorporating d4-CBZ and d4-CBZE as internal standards, allows precise and accurate determination of the analytes with good reproducibility and stability.

Tissue distribution of phenoxybenzamine in the rat. Lack of adipose tissue storage.

Rats were given the basic lipophilic drug, phenoxybenzamine, in single i.v. doses of 0.4 and 30 mg/kg. The drug was determined in plasma and 7 tissues by a new HPLC method. Adipose tissue reached peak levels after 30 minutes. At that time levels in heart, kidney, and brain were higher than in subcutaneous, epididymal, and mesenteric adipose tissues. The percentage metabolites in adipose tissue, kidney, and liver was 0, 88, and 96, respectively. Pretreatment with SKF 525-A inhibited metabolism and increased the tissue levels of unchanged drug, however, even under these conditions storage in adipose tissues did not occur, the adipose storage index being still less than unity. These results contradict findings of the 1950s which have been repeatedly reported in textbooks and reviews, but they confirm observations that basic drugs, even when highly lipophilic, are not being stored in adipose tissues.