Lamotrigine in pregnancy: clearance, therapeutic drug monitoring, and seizure frequency.

OBJECTIVE: To characterize the magnitude and course of alterations in total and free lamotrigine (LTG) clearance (Cl) during pregnancy and the postpartum period, to assess the impact of therapeutic drug monitoring (TDM) on seizure frequency, to determine the ratio to individual target LTG concentration that is associated with increased seizure risk, and to evaluate maternal postpartum toxicity. METHODS: A cohort of women were enrolled before conception or during pregnancy in this prospective, observational study. Visits occurred every 1 to 3 months with review of seizure and medication diaries, examination, and blood sampling. Total and free LTG Cls were calculated. Individualized target concentrations were used for TDM. The ratio to target concentration (RTC) was compared between patients with and without increased seizures. A receiver operating characteristic curve determined the threshold RTC that best predicts increased seizure frequency. RESULTS: Analysis of 305 samples in 53 pregnancies demonstrated increased total and free LTG Cl in all trimesters above nonpregnant baseline (p < 0.001), with peak increases of 94% and 89% in the third trimester. Free LTG Cl was higher in white compared with black women (p < 0.05). Increased seizure frequency (n = 36 women with epilepsy) in the second trimester was associated with a lower RTC (p < 0.001), and RTC < 0.65 was a significant predictor of seizure worsening. An empiric postpartum taper reduced the likelihood of maternal LTG toxicity (p < 0.05) (n = 27). Newborn outcomes were similar to the general population (n = 52). CONCLUSIONS: These novel data contribute to a rational treatment plan and dosing paradigm for lamotrigine use during pregnancy, parturition, and the postpartum period.

Comparative analysis of PAH:DNA adducts formed in lung of mice exposed to neat coal tar and soils contaminated with coal tar.

7H-Benzo[c]fluorene (benzo[c]fluorene) is a major DNA adduct forming component of coal tar in lung of mice. The present study evaluated the types of PAH:DNA adducts formed from different neat coal tar samples and soils contaminated with coal tar. Mice were fed diets containing coal tar either neat or as a contaminant in an environmental soil sample for 14 days, and the types of chemical:DNA adducts formed in lung were evaluated using 32P-postlabeling and HPLC analysis. Three major DNA adducts derived respectively from benzo[b]fluoranthene (B[b]F), benzo[a]pyrene (B[a]P), and benzo[c]fluorene were detected in three of the four neat coal tar samples evaluated. In contrast, only a single major DNA adduct derived from benzo[c]fluorene was observed with the remaining tar sample. Ingestion of coal tar contaminated soil resulted in DNA adducts primarily derived from benzo[c]fluorene and B[b]F; a B[a]P derived DNA adduct was not detected. The DNA adducts derived from benzo[c]fluorene and B[b]F but not B[a]P were also observed with animals fed methylene chloride extracts of three of these soils but not the one designated A1000H soil. However, the extract of A1000H resulted in a B[a]P:DNA adduct being detected along with adducts formed from B[b]F and benzo[c]fluorene. The selective formation of the benzo[c]fluorene:DNA adduct with coal tar contaminated soils indicates that the in vivo systemic bioavailability and/or metabolism of benzo[c]fluorene is relatively high when compared to other DNA adducting hydrocarbons within coal tar. Benzo[c]fluorene may play a critical role in the potential of contaminated soil to induce a toxicological response in animals.

7H-benzo[c]fluorene: a major DNA adduct-forming component of coal tar.

Coal tar is a complex mixture that exhibits high carcinogenic potency in lungs of animals when administered in the diet. Studies have noted that lung tumor induction does not correlate with the benzo[a]pyrene content of coal tar, suggesting that other hydrocarbons may be involved in the observed tumorigenicity. Our previous studies have demonstrated that a major 'unknown' chemical-DNA adduct is formed in the lung of mice exposed to coal tar. We have used an in vitro rat microsomal activation system to generate the 'unknown' adduct with neat coal tar and fractions of coal tar obtained by chemical fractionation and HPLC. Chemical-DNA adduct formation was evaluated by (32)P-postlabeling using both multi-dimensional TLC and HPLC. GC-MS analysis of the coal tar fractions obtained from HPLC, which produced the 'unknown' adduct in vitro, demonstrated that the adducting hydrocarbon had a mass of 216. A careful evaluation of candidate hydrocarbons led to the conclusion that a benzofluorene derivative may be responsible for forming the 'unknown' chemical-DNA adduct. Comparative in vitro and in vivo studies on the adducting properties of all three isomers of benzofluorene indicated that 7H-benzo[c]fluorene is responsible for producing the 'unknown' adduct observed in the lung of mice ingesting coal tar. Animal feeding studies also demonstrated that 7H-benzo[c]fluorene formed considerably more lung DNA adducts than 11H-benzo[a]fluorene and 11H-benzo[b]fluorene. These data indicate that the four-ring polycyclic aromatic hydrocarbon 7H-benzo[c]fluorene, a hydrocarbon not previously shown to form DNA adducts in lung, is in fact a potent lung DNA adductor and is a candidate PAH for causing lung tumors in animals treated with coal tar.

Differences in the tumorigenic activity of a pure hydrocarbon and a complex mixture following ingestion: benzo[a]pyrene vs manufactured gas plant residue.

The tumorigenic activity of manufactured gas plant residue (MGP) was evaluated in female A/J mice using a F0927 basal gel diet system. Adulterated diets containing MGP (0.10% or 0.25%) or benzo[a]pyrene (B[alpha]P; 16 or 98 ppm) were fed for 260 days. A negative control group was maintained on a nonadulterated basal gel diet. Mice dosed with a single ip injection of 1.79 mg of B[a]P in a tricaprylin vehicle and maintained on a NIH-07 pellet diet were positive controls. In addition, a nontreated group of mice and a group dosed with vehicle only were maintained on a NIH-07 pellet diet and used as negative controls. Animal body weight and consumption of MGP and B[a]P were monitored throughout the study. Ingestion of a 0.10 or 0.25% MGP adulterated diet resulted in 70 and 100% of the mice developing lung tumors with a multiplicity of 1.19 and 12.17 tumors/mouse, respectively. Mice maintained on a 0.10% MGP diet consumed 0.7 g of MGP containing 1.8 mg of B[a]P while those fed a 0.25% MGP diet ingested 1.5 g of MGP containing 4.2 mg of B[a]P. The incidence of lung tumors in mice fed only B[a]P was considerably lower than that observed for animals fed a MGP diet. A diet containing 98 ppm B[a]P produced a significant incidence of tumor-bearing mice with 52% developing lung tumors. The multiplicity observed in these animals, however, was not significant at 0.59 tumors/mouse. A diet containing 16 ppm B[a]P did not produce a significant tumorigenic response in lung. Animals fed a 16 or 98 ppm B[a]P diet consumed a total of 11 and 67 mg of B[a]P, respectively. A single ip dose of B[alpha]P (1.79 mg in 0.25 mL of tricaprylin) resulted in 100% lung tumorigenesis with a multiplicity of 15.79 tumors/mouse. In contrast to observed induction of lung tumors, no forestomach tumors were detected in any animal fed a 0.10 or 0.25% MGP adulterated diet. However, ingestion of a diet containing only 16 or 98 ppm of B[a]P resulted in 20 and 100% of the mice developing forestomach tumors, respectively. The multiplicity for forestomach tumors was 0.24 and 4.22 tumors/mouse, respectively. The incidence of forestomach carcinomas in tumor bearing mice was 8 and 52%, respectively. The ip administration of 1.79 mg of B[a]P resulted in an 83% forestomach tumor incidence having a multiplicity of 1.83 tumors/mouse. Forestomach carcinomas were induced in 34% of the mice exhibiting forestomach tumors. These data indicate that chronic ingestion of MGP- or B[a]P-adulterated diets produces significant differences in the tumorigenic response of female A/J mouse forestomach and lung tissues.