The pharmacokinetics and pharmacodynamics of the prodrug ramipril and its active ACE-inhibiting metabolite ramiprilat were investigated in an open, randomised, three-way cross-over study in 12 healthy male volunteers. Subjects received 2.5 mg ramipril orally, 2.5 mg ramipril intravenously and 2.5 mg ramiprilat intravenously. The absolute bioavailability as judged by ramipril plasma AUC was 15%, by ramiprilat plasma AUC, 44%. Ramiprilat formation from intravenous ramipril was 53% and from oral ramipril 28%. Urinary recovery of oral ramipril was 23%, i.v. ramipril 49%, and i.v. ramiprilat 68% of the given dose. Maximum ACE inhibition was highest (100%) after i.v. ramiprilat; it was 99% after i.v. ramipril and 84% following oral ramipril. ACE inhibition over 24 h was highest after i.v. ramipril, 2% less with i.v. ramiprilat and 34% less with oral ramipril. Ramiprilat renal clearance was concentration dependent. The biological availability of ramipril can best be judged by ramiprilat AUC, urinary recovery of ramipril and metabolites, or ACE inhibition over 24 h. It is concluded that the bioavailability of oral ramipril seems to be in the range of 44-66%.

SummaryAn enzyme immuno assay was developed to measure complexes of tissue-type plasminogen activator (t-PA) with C1-inhibitor in order to study the role of C1-inhibitor as an inhibitor of t-PA in plasma. In vitro experiments with melanoma and recombinant t-PA learned that purified C1-inhibitor reacts with both single chain t-PA and two chain t-PA. The rate constants ranged from 3.0 to 5.2 M-1s-1 In plasma, melanoma and recombinant two chain t-PA were hardly inhibited by C1-inhibitor, in contrast to melanoma and recombinant single chain t-PA which were inhibited to the same extent by endogenous C1-inhibitor as they were by purified C1-inhibitor. In vivo, t-PA/C1-inhibitor complex could be measured in plasma in a few cases in healthy volunteers (0.62 ± 0.43 ng/ml t-PA equivalents), after exercise (0.84 ± 0.25 ng/ml t-PA equivalents) and after a desmopressin infusion (0.26 ± 0.04 ng/ml t-PA equivalents). However, t-PA/C1-inhibitor complex was found in plasma in all cases after venous occlusion (1.7 ± 0.5 ng/ml t-PA equivalents), in peritoneal fluid from patients suffering from peritoneal inflammatory disease (2.2 ± 1.3 ng/ml t-PA equivalents) and in plasma from healthy volunteers during a t-PA infusion (27.7 ± 18.5 ng/ml t-PA equivalents at peak level). In the last case, about 8 % of the infused dose of recombinant t-PA (alteplase) was inhibited by C1-inhibitor at peak level. The half-life (t1/2α) of t-PA antigen in plasma was found not to be altered when t-PA was inhibited by C1-inhibitor (4.0 min and 4.2 min, respectively). Thus, in vivo, t-PA/C1-inhibitor complex is mostly present when t-PA escapes rapid liver clearance and accumulates in one place (e.g. during venous occlusion or in peritoneal fluid) or when it circulates in high concentrations (e.g. during t-PA infusion).

Warfarin has no effect on the pharmacokinetics of napsagatran, but has a marked influence on the pharmacodynamic parameters (APTT, PT) of napsagatran. In clinical practice, this interaction between the two compounds should be taken into account. The PT cannot be used to monitor the effect of oral anticoagulants during the switch from this group of direct thrombin inhibitors to full oral anticoagulant therapy.

The oral bioavailability of PPS is negligible in young healthy males.

1. The anti‐clotting effects after intravenous administration of three low molecular weight (LMW) heparins, Fragmin (KABI 2165), Fraxiparine (CY 216), Clexane (PK 10169) and the LMW mixture of glycosaminoglycuronans Orgaran (Org 10172) were compared in a randomized cross‐over study in 12 healthy male volunteers. 2. The time courses of the anti‐Xa activity of Fragmin, Fraxiparine and Clexane (five subjects) were best fitted by a monoexponential function and had comparable half‐lives of 1.9 h, 2.3 h and 2.8 h, respectively. The time courses of the anti‐Xa activity of Orgaran and Clexane (four subjects) were described by a biexponential function with terminal half‐lives of 56.8h and 27.7 h, respectively. They were longer than those of Fraxiparine and Fragmin. Orgaran injection was associated with a significantly smaller 'clearance' (0.8 +/‐ 0.2 l h‐1) of the plasma anti‐Xa activity compared with Fragmin (2.0 +/‐ 0.5), Fraxiparine (1.7 +/‐ 0.5) and Clexane (1.6 +/‐ 0.5). 3. In comparison with the three LMW heparins, the terminal half‐life of plasma anti‐IIa activity after Orgaran was longer and the 'clearance' of Orgaran was lower than that after Clexane. The area under the curve of the plasma anti‐IIa activity after administration of Orgaran was negligible compared with that obtained after injection of the LMW heparins. 4. Orgaran caused the smallest and Fragmin the greatest prolongation of the activated partial thromboplastin time (Orgaran 5.8 +/‐ 1.2 s vs Fragmin 18.5 +/‐ 5.2 s) and the thrombin clotting time (Orgaran 2.9 +/‐ 1.7 s vs Fragmin 47.8 +/‐ 0.9 s).(ABSTRACT TRUNCATED AT 250 WORDS)