# Pharmacokinetics of Marine-Derived Drugs
## 4 Pharmacokinetics Studies in Humans
Similar to previous research, linear kinetics for C\({}_{\rm max}\) and AUC, as well as narrow V\({}_{\rm ss}\) (5.55 L) and a short T\({}_{1/2}\) (0.52 h), were observed. The increases in Cl and V\({}_{\rm ss}\) were strongly correlated with body size and were best predicted with body surface area and height. In a subsequent study, the pharmacokinetics of kahalalide F was reported from a phase II study in patients with advanced malignant melanoma. Patients were infused weakly for one hour i/v with kahalalide F at a dose of 650 ug/m\({}^{2}\). The median V\({}_{\rm ss}\) was 7.0 L, and median T\({}_{1/2}\) was 0.46 h [162]. The pharmacokinetics of an antineoplastic alkaloid ecteinascidin 743 (syn. trabectedin) (**25**) isolated from _Ecteinascidia turbinate_ (Caribbean sea squirt) was studied in patients with solid tumors. Patients were administered multiple doses (50-900 ug/m\({}^{2}\)) of ecteinascidin 743 by 24 h i/v infusion. The C\({}_{\rm max}\) (0.06-0.95 ng/mL) and AUC (1.2-36 ng/mL) increased linearly with increasing dose. Dose- normalized AUC was independent of dose. This suggests the linear pharmacokinetics of ecteinascidin 743. The pharmacokinetic was also linear after 21 days of five repeated courses. The T\({}_{1/2}\) increased up to a dose of 400 ug/m\({}^{2}\), and then decreased. An increase in the clearance after five consecutive courses was registered. At doses of 50-100 ug/m\({}^{2}\), the concentration of drugs at the terminal time point was under the limit of quantification. The hepatic toxicity of drugs increased with AUC. All data were characterized by considerable interpatient variability. Considering all results together, the authors suggested that a 24 h i/v every 3 weeks is a well-tolerated and appropriate course of treatment [163]. The pharmacokinetics of a antineoplastic alkaloid trabectedin (syn. ecteinascidin 743) (**25**) was studied in patients after continuous 24 h intravenous infusion of the drug at a dose of 1.3 mg/m\({}^{2}\). The maximal concentration (0.6 ng/mL) was observed at 8 h and was maintained at this level until 24 h after injection. The AUC was 16.5 ng-h/mL; Cl and T\({}_{1/2}\) were 51.3 L/h/m\({}^{2}\) and 31.9 h, respectively [164]. The results of this experiment allowed recommending a treatment scheme for patients with liposome. In another trial, trabectedin (ecteinascidin 743) was injected by infusion over 1 or 3 h every 21 days to 44 patients with solid tumors. The clearance of trabectedin was not linear over the course of the 1 h infusion schedule. It was not significantly dependent on the dose with the 3 h infusion schedule and did not vary significantly. The AUC showed a linear increase with the dose. The observed hepatotoxicity was significantly associated with higher C\({}_{\rm max}\) values. The results of this trial suggested a 1650 ug/m\({}^{2}\) dose of trabectedin for 3 h infusion [165]. [PERSON] et al. reported the results of pharmacokinetic studies of histochrome (**17**). Histochrome (1%; 100 mg) was injected intravenously in the seven subjects. The pharmacokinetic data indicated that histochrome has a relatively high AUC (665.6 ug-h/mL), a high volume distribution in plasma (5.7 L), and low clearance (0.16 L/h). The first maximum of the drug in plasma was followed by a second one after 26 h. The authors stated that enterohepatic recirculation over the 2-6 h period leads to prolongation of the elimination half-life (T\({}_{1/2}\)) up to 87.3 h and MRT up to 131.4 h. Presumably, the substance accumulates in adipose tissue, which may explain the prolongation of T\({}_{1/2}\) and MRT. The study confirmed the rationality of the therapeutic dose selection [166]. A large number of experiments have been performed with fucoidans (**1**). The studies on animals confirmed that high-molecular-weight fucoidan is absorbed after peroral and transdermal application and distributed in tissues and organs [27; 28].