Prenatal cocaine exposure and childhood psychopathology: a developmental analysis.

A rising number of children exposed to cocaine in utero are substantially vulnerable to mortality and morbidity expressed in a variety of physical, cognitive, emotional, motor, and social problems. Research on developmental outcomes in such children is reviewed and the interaction of prenatal and postnatal environmental factors, with a focus on the parent-child-environment transactional system, is discussed. Related societal and treatment issues are highlighted.

Biotransformation of nifedipine in rat and dog.

Following oral and/or intraduodenal administration, the biotransformation of 14C-labelled nifedipine (dimethyl 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-pyridine-3, 5-dicarboxylate, Bay a 1040, Adalat, CAS 21829-25-4) has been reinvestigated in rats and dogs (dose: 5 mg/kg body weight in both species) to complete the metabolic data. Thirteen metabolites were isolated from the perfusate and bile of the isolated perfused rat liver model. Their structures were elucidated by spectroscopic methods (FAB-MS, combined GC/MS, NMR). The analyzed samples were used for the chromatographic (HPLC) comparison with urine and bile from the in vivo studies. The metabolites identified in rat urine (oral dose) account for 47.4% of the dose administered. 82.8% (rat) and 62.8% (dog) of the dose, resp., could be attributed to known structures in urine and bile following intraduodenal administration. Based on the structures identified the following biotransformation steps occurred: dehydrogenation of the 1,4-dihydropyridine system, hydroxylation of the methyl groups at 2- or 6-position followed by glucuronidation or by subsequent oxidation to the carboxylic acid, and oxidative ester cleavage.

Biotransformation of nitrendipine in rat, dog, and mouse.

14C-Labelled Nitrendipine (Bay e 5009; Baypress, Bayotensin; CAS 39562-70-4) was administered by the oral and intraduodenal route to rats, dogs, and mice (oral dosing only) to elucidate the biotransformation pathways in these three species. The drug was extensively metabolized: 20 biotransformation products were identified by comparison with synthetic reference compounds using two-dimensional TLC, HPLC, GC/radio-GC, combined GC/MS (EI-, CI-mode), FAB-MS, and 1H-NMR-spectroscopy. The metabolites identified accounted for approx. 72 to 73% of the dose administered in rats and dogs (bile and urine) and 48 to 56% in male and female mice (urine only). Based on the structures identified the following biotransformation reactions occurred: Dehydrogenation of the 1,4-dihydropyridine (primary metabolic step), oxidative ester cleavage as further basic biotransformation reaction (also at the dihydropyridine state), hydroxylation of the methyl groups in 2- or 6-position as separated and important metabolic reaction (at the dihydropyridine as well as pyridine state), reduction of the aromatic nitro group (important only in mice) and subsequent acetylation (dog only), and glucuronidation as phase II reaction forming ether and ester type glucuronides.

Biotransformation of nimodipine in rat, dog, and monkey.

14C-labelled (+/-) 3-isopropyl5-(2-methoxyethyl)1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl)-pyridine-3,5-dicarboxylate (nimodipine, Bay e 9736, Nimotop; CAS 66085-59-4) was administered orally to rat, dog, and monkey (each 5, 10, or 20 mg/kg) and intraduodenally to rat (5 mg/kg). Urine was collected over a period of 24 h (bile 6 h). Dog bile was obtained from the gall bladder 4 h after oral dosing. Rat plasma was taken 1 h p. appl. of the unlabelled compound and additionally at different times following administration of [14C]nimodipine. The metabolite profiles in the excreta were established by TLC (radioscan/autoradiography). The unchanged drug was neither detectable in urine nor in bile, but was present in rat plasma. Nimodipine was extensively metabolized. 18 metabolites were isolated by LC, HPLC, and preparative TLC and identified by comparison with the reference substances using two-dimensional TLC, HPLC, GC/radio-GC, 1H-NMR-spectroscopy, MS, and GC/MS. About 75% of the renally excreted biotransformation products, more than 50% of the metabolites present in the bile (rat, dog) and approx. 80% of the plasma metabolites (rat only) have been identified. The large number of metabolites was produced by some common biotransformation reactions: dehydrogenation of the 1,4-dihydropyridine system, oxidative ester cleavage, oxidative O-demethylation and subsequent oxidation of the resulting primary alcohol to the carboxylic acid, hydroxylation of the methyl groups at 2- or 6-position, hydroxylation of one methyl group of the isopropyl ester moiety, reduction of the aromatic nitro group, and glucuronidation as phase II-reaction.

Metabolic fate of rioprostil in the rat--in vivo and in liver perfusion.

The metabolic fate of rioprostil is investigated in the rat--in vivo and in liver perfusions--using the tritriated drug. Seven metabolites are isolated from the perfusion model and identified by 1H-NMR spectroscopy, mass spectrometry (EI/CI/FAB) and combined GC-MS (EI/CI). Rioprostil is extensively metabolized. The main metabolite in urine (81.2%) and bile (50.1%) is the tetranor-1,16-dicarboxylic acid. The tetranor carboxylic acid is isolated in smaller amounts (8.1 and 18.2% resp.). Rioprostil itself can be detected neither in the urine nor in the bile of the in vivo studies. Thus, the metabolism of rioprostil proceeds via the biotransformation pathways of the naturally occurring prostaglandins.

Pharmacokinetics of nisoldipine. III. Biotransformation of nisoldipine in rat, dog, monkey, and man.

After intraduodenal administration of 14C-labelled (+/-) 3-isobutyl-5-methyl 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-pyridine-3,5-dicarboxylate (nisoldipine, Bay k 5552) to rats approx. 68% of the dose was excreted in the bile in the first 6 h. In an isolated perfused rat liver model the excretion with the bile was 56% of the total dose within 3 h. The recovery of radioactivity from orally administered [14C] nisoldipine was approx. 32% (rat), 23% (dog), 73% (monkey) and 74% (man), resp., in the urine. The unchanged drug was neither detected in the urine nor in the bile, but nisoldipine was present in plasma of the rat 30 min after dosing and up to 24 h in man. The drug was extensively metabolized: 18 biotransformation products were identified by comparison with synthetic reference compounds using combined GC-MS, 1 NMR-spectroscopy, mass spectrometry, gas chromatography/radio-gas chromatography and two-dimensional thin layer chromatography, 6 of them being quantitatively important (about 80% of the radioactivity excreted in urine). The metabolites identified accounted for approx. 82% (rat: bile and urine), 19% (dog, due to the low renal excretion), 58% (monkey: urine) and 64% (man: urine) of the excreted dose, resp. The following biotransformation steps occurred: hydroxylation of the isobutyl moiety, dehydrogenation of the 1,4-dihydropyridine system, oxidative ester cleavage, hydroxylation of one of the methyl groups in 2- or 6-position and subsequent oxidation to the carboxylic acid, oxidation of one of the methyl groups of the isobutyl moiety to the carboxyl group reduction of the aromatic nitro group (minor biotransformation reaction) and glucuronidation as phase II reaction.

Nitrendipine: identification and synthesis of main metabolites.

(+/-)-Ethylmethyl-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate (nitrendipine, Bay e 5009) 1, a calcium antagonistic 1,4-dihydropyridine derivative, is currently under development as an antihypertensive. A pharmacokinetic study with 14C-nitrendipine in the rat revealed as major metabolites the pyridine 2, 3, 4, 5, 6 and 9 using glc-, tlc- and gc/ms-techniques. A potential metabolic pathway is discussed involving oxidation to the pyridine form, saponification of the ester groups and hydroxylation of the methyl groups as general biotransformation steps. 1,4-Dihydropyridines bearing appropriate functionalities were precursors in the synthesis of the reference metabolites 2, 3, 4, 7, 8 and 10.

Nimodipine: synthesis and metabolic pathway.

Key step of the synthesis of the calcium antagonistic cerebral vasodilator (+/-) isopropyl-2-methoxyethyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate (Bay e 9736, nimodipine) (5) is the cyclizing Michael addition of 3 onto 4. A pharmacokinetic study with 14C-nimodipine in the rat revealed as major metabolites the dihydropyridines 6 and 8 as well as the pyridines 7, 9, 10, 11, 13 and 14. A potential metabolic pathway is discussed involving ether cleavage and oxidation to the pyridine form as primary biotransformation steps. Reference metabolites were synthesized using 1,4-dihydropyridines with appropriate functionalities as precursors.