# Pharmacokinetics of Marine-Derived Drugs
## 4 Pharmacokinetics Studies in Humans  
To date, pharmacokinetic studies in humans have been conducted for very few marine-derived compounds. Most of these molecules are in different stages of clinical trials or are approved for medicinal use. Among others, the anticancer compounds are most promising. The pharmacokinetics publications about anticancer marine-derived molecules are predominant. Most of these investigations have been a continuation of pharmacokinetic experiments in animals. As a continuation of pre-clinical studies of aplidine and its pharmacokinetics in vivo, several pharmacokinetic studies have been conducted in subjects with advanced tumors. Aplidine (**18**) was administered in infusions (0.13-8.00 mg/m\({}^{2}\)) by different schemes (1 or 24 h weekly; 3 or 24 h biweekly; 1 h for 5 consecutive days every 3 weeks). The group of 48 patients with solid tumor or non-Hodgkin's lymphoma was enrolled in the phase I of clinical trials. The relatively long T\({}_{1/2}\) (up to 43.8 h), prolonged MRT (up to 51 h), Cl (up to 6.2 L/h), and high V\({}_{\text{ss}}\) in the blood (up to 144.6 L) were observed in subjects after intravenous infusion of aplidine at the doses of 0.2-8 mg/m\({}^{2}\) for 24 h. The aplidine concentration in plasma was lower compared to that in blood. The AUC and C\({}_{\text{max}}\) increased with increasing dose. The unchanged drug is excreted with urine (average recovery was ~15% over 48 h) [157]. Similar pharmacokinetic data were later reported by [PERSON] et al. [158] who performed experiments with radiolabeled \({}^{14}\)C aplidine on six patients. Clinical data confirmed previous results observed in animals that aplidine is accumulated in red blood cells. The accumulation was linear up to doses of 5 mg/m\({}^{2}\). The drug undergoes moderate microsomal-mediated metabolism, [159]. Based on these results, the recommended doses of aplidine were suggested as 5 and 7 mg/m\({}^{2}\). During phase I of clinical trials, the pharmacokinetics of dolastatin 10 (**20**) was evaluated on a cancer patient after a 30 s bolus i/v injection at a dose of 65 ug/m\({}^{2}\). The maximal concentration of dolastatin 10 (29.3 ng/mL) was detected 5 min after injection. The plasma concentration-time function was three-exponential with a t\({}_{1/2~{}\alpha}\) of 0.087 h, t\({}_{1/2~{}\beta}\) of 0.69 h, and t\({}_{1/2~{}\gamma}\) of 8 h. The plasma clearance was 3.7 L/h/m\({}^{2}\) and V\({}_{\rm ss}\) was 46.7 L/m\({}^{2}\). The metabolite N-dimethyl dolastatin 10 with m/z 772 was detected in the plasma from 0.75 to 1.5 h. The concentration of metabolite was approximately 1/50 th the concentration of dolastatin 10 [153]. The pharmacokinetic data acquired for kahalalide F (**19**) in animal experiments were applied in phase I clinical trials. A group of 32 subjects with advanced androgen refractory prostate cancer received an intravenous injection of infusion (20-930 ug/m\({}^{2}\)) over one hour during five consecutive days every three weeks. The human pharmacokinetics patterns were similar to those observed in animals. The maximal concentration of drug was registered in blood at the end of infusion (C\({}_{\rm max}\) was 37.9-183.7 ng/mL, AUC was 28.0-53.4 ng/mL) and characterized by dose linearity up to 560 ug/m\({}^{2}\) per day. Drug elimination was rapid (T\({}_{1/2}\) = 0.47-0.88 h, Cl = 14.5-6.9 L/h) and was dose dependent; the mean V\({}_{\rm ss}\) was 7.0 L. Similar to the in vivo results, kahalalide F did not accumulate during the course. The sensitivity of the analytical method was unable to determine the urinary excretion of the drug. Considering these data and based on toxicology, the rational dose of kahalalide F was determined to be 560 ug/m\({}^{2}\)/day [160]. [PERSON] et al. investigated the pharmacokinetics of kahalalide F in 35 patients with advanced solid tumors after intravenous injection once-weekly as a 1 h infusion [161].