Ninja Nerd- Pharmacokinetics: Absorption and Bioavailability – Comprehensive Notes (Transcript Summary)

Absorption: routes of administration and basic concepts

• Absorption definition: the process by which a drug administered via a route enters the circulation.

• Routes of administration to know (order not strictly required):

  • PO (oral) – gastrointestinal (GI) route.

  • Rectal administration (suppositories) – another GI route.

  • Parenteral injections:

  • Intradermal (into the dermis).

  • Subcutaneous (Sub-Q).

  • Intramuscular (IM).

  • Topical – local action on skin (epidermis and underlying tissues).

  • Intravenous (IV) – directly into the bloodstream (no membrane crossing required).

  • Inhaled – via lungs.

  • Buccal – between lip and teeth.

  • Sublingual – under the tongue.

• The most clinically relevant routes to memorize:

  • PO (outpatient common).

  • IV (inpatient, direct bloodstream).

  • Subcutaneous or intramuscular injections (common but still require absorption).

• Key point: IV administration bypasses absorption barriers and delivers 100% of the dose into systemic circulation; other routes must cross membranes and are subject to absorption issues.

• When a drug is taken (often PO), to reach the bloodstream it must be absorbed through the GI lining and membranes, which involves crossing cell membranes via specific transport mechanisms.\

  The four primary mechanisms of crossing a biological membrane (relevant to GI absorption):

  • Passive diffusion: high to low concentration, small and hydrophobic (lipophilic) molecules diffuse easily across lipid bilayers.

  • Important characteristics: small size, hydrophobicity (nonpolar).

  • Facilitated diffusion: high to low concentration, but requires a carrier protein (no energy). Used by hydrophilic or larger molecules that cannot pass directly through the lipid bilayer.

  • Active transport: low to high concentration, carrier proteins plus energy (ATP) are required; moves substances against their gradient.

  • Endocytosis (including receptor-mediated endocytosis): large molecules that are too big to cross membranes directly are brought into cells via vesicle formation; can involve receptors on the cell surface (example: B12).

  • Example in notes: B12 can be transported via receptor-mediated endocytosis.

• A summary of absorption mechanisms for PO route (four options):

  • Passive diffusion

    • high to low, small + hydrophobic

  • Facilitated diffusion

    • high to low, needs carrier protein

  • Active transport

    • low to high, needs energy (ATP)

  • Endocytosis

    • very large molecules, receptor-mediated

• Important caveat: the only route that bypasses crossing membranes entirely is IV administration; IV avoids the four membrane-crossing steps.

• Practical takeaway: absorption depends on drug properties (size, lipophilicity, charge) and route of administration (which membranes must be traversed).

• Conceptual metaphor mentioned in lecture: the intestinal surface area can be imagined like a tennis court stretched out to maximize absorption area.

• Route-specific considerations:

  • Injections (intradermal, subcutaneous, IM) must pass through tissue layers to reach nearby vasculature before entering blood; IV goes straight into the blood.

  • Topical and transdermal routes deliver local or systemic effects but still rely on crossing skin barriers for systemic absorption.

• pH- and environment-dependent absorption (overview): absorption is influenced by drug ionization state, which is controlled by pH; non-ionized (uncharged) forms cross membranes more readily than charged forms.

• Summary statement: Absorption mechanisms for oral/PO routes include passive diffusion (small, nonpolar), facilitated diffusion (needs carrier for larger or polar drugs), active transport (ATP-dependent, against gradient), and endocytosis (large molecules). IV is the exception that bypasses membrane crossing entirely.

Mechanisms of Absorption Across Membranes (with examples)

• Passive diffusion

  • From lumen to blood via the GI epithelium, driven by a concentration gradient.

  • Requires the drug to be small and hydrophobic (lipid-soluble).

• Facilitated diffusion

  • Uses carrier proteins; still follows a concentration gradient (high to low).

  • Useful for larger or more polar molecules that cannot diffuse directly through the lipid bilayer.

• Active transport

  • Moves substances from low to high concentration (against gradient) using energy (ATP).

  • Used for certain essential nutrients or large hydrophilic molecules; not all drugs use this route.

• Endocytosis (including receptor-mediated endocytosis)

  • Large molecules (e.g., B12) can be taken up via vesicle formation after binding to surface receptors.

  • Then endocytosed material can be released on the basolateral side into the vasculature.

• Example mentioned: B12 as an illustration of endocytosis for a large molecule.

Factors that Affect Absorption

• pH and drug form (ionization state) influence absorption via Le Chatelier’s principle:

  • Weak acids (HA) exist in two forms: nonpolar/uncharged (HA) and polar/charged (A− after dissociation).

    • A- is not easily absorbed

    • To enhance absorption, increase acidity in the gastrointestinal tract (specifically proximal duodenum), which will promote the nonpolar form of the weak acid, thereby facilitating greater absorption into the bloodstream.

  • Weak bases exist in two forms: protonated (BH+), which is polar, and unprotonated (B), which is nonpolar.

  • The nonpolar/uncharged form crosses membranes more readily; the charged form does not.

  • For weak acids, acidic environments push the equilibrium toward the nonpolar HA form, increasing absorption.

  • For weak bases, alkaline environments push the equilibrium toward the nonpolar B form, increasing absorption.

• Practical implications for weak acids and bases:

  • Weak acids best absorbed in acidic environments (e.g., proximal duodenum) where there are more protons to bias toward HA (nonpolar form).

  • Weak bases best absorbed in alkaline environments (e.g., distal ileum) where there are fewer protons to bias toward BH+ (polar form).

• Specific examples discussed:

  • Aspirin (a weak acid) would be best absorbed in acidic GI regions (proximal small intestine).

  • Amphetamines (weak bases) would be better absorbed in more alkaline regions like the distal ileum.

• Blood flow effects:

  • Adequate perfusion to GI tract and skin is necessary for absorption; reduced blood flow (e.g., in shock: septic, cardiogenic, hypovolemic) reduces absorption for orally administered, rectal, and cutaneous routes.

  • In shock, IV administration is preferred because it bypasses absorption barriers and guarantees drug delivery to systemic circulation.

• Total surface area and contact time:

  • Greater surface area and longer contact time increase absorption; conditions that decrease contact time (e.g., diarrhea) reduce absorption; constipation increases contact time and can increase absorption.

  • Diseases that destroy microvilli, villi, or brush border (e.g., inflammatory bowel disease, celiac disease, gastroenteritis) decrease surface area and reduce absorption.

• P-glycoprotein (P-gp) and multi-drug resistance:

  • P-gp on the apical surface of GI epithelium can pump certain drugs back into the lumen, decreasing absorption.

  • This mechanism contributes to reduced drug absorption in some multi-drug resistant situations.

• Net summary: pH, blood flow, surface area, contact time, and transporter proteins (P-gp) all modulate absorption; their effects depend on route and drug properties.

Bioavailability (F)

• Definition: fraction of an administered dose that reaches the systemic circulation in an active form.

• IV bioavailability:

  • When a drug is given IV, the entire dose enters systemic circulation (F = 100%). Does not pass through any absorption mechanisms.

• Other routes (e.g., PO):

  • Absorbed amount is influenced by absorption, first-pass metabolism (hepatic), solubility, instability in the GI tract, and transporter effects; not all of the administered dose reaches systemic circulation.

Quantitative comparison using AUC (area under the curve):

F = (AUC PO Administration) / (AUC IV Administration) X100%

• AUCPO is the area under the concentration-time curve after oral administration; AUCIV is the area after IV administration.

• If IV administration yields 100 mg reaching the bloodstream, and PO yields only 50 mg equivalent in systemic circulation (as reflected by AUC), then F=\frac{50}{100}x100\% = 50%

• Examples and consequences:

  • Solubility and lipid solubility: lipophilic, smaller molecules tend to have higher absorption and thus higher bioavailability; hydrophilic, larger molecules tend to have lower bioavailability.

  • Instability: gastric pH or proteolytic enzymes can degrade oral drugs before absorption (e.g., penicillin G degraded by gastric acid (patient will get 0% PCN G); penicillin G often given IM/IV because of instability in the stomach).

  • First-pass effect (hepatic portal circulation): after GI absorption, drugs pass through the portal vein to the liver; the liver metabolizes a portion of the drug before it reaches systemic circulation, reducing observed bioavailability.

  • Insulin example: orally administered insulin would be degraded by GI proteases, leading to negligible bioavailability; hence insulin is given IV or by other non-oral routes.

• First-pass effect and the hepatic portal system:

  • The portal system transfers drug from GI tract to the liver before entering systemic circulation.

  • The liver may metabolize a portion of the drug, reducing systemic availability.

  • Drugs given via routes that bypass first-pass (e.g., sublingual, IV, transdermal, some rectal routes) avoid this metabolism and thus have higher observed bioavailability.

• Nitroglycerin example (illustrative of first-pass effects):

  • When given PO, a large portion is destroyed by first-pass metabolism in the liver, leaving only a small fraction to reach systemic circulation. A classic example notes that PO nitroglycerin can have as little as 10% of the dose reaching systemic circulation (e.g., 100 mg PO → ~10 mg systemic).

  • Sublingual administration bypasses the liver and delivers a larger fraction into systemic circulation, providing rapid relief of anginal pain.

  • If nitroglycerin is given IV, essentially 100% reaches systemic circulation (no first-pass metabolism).

• Factors that modulate bioavailability (summarized):

  • Solubility/lipid solubility: higher lipid solubility and smaller size generally increase F.

  • Instability in GI tract or liver: degradation reduces F.

  • First-pass metabolism: reduces F for oral forms; routes that bypass first-pass increase F.

• Practical implications for route choice:

  • For drugs susceptible to GI degradation or significant first-pass metabolism, non-oral routes (IV, IM, sublingual, transdermal) are preferred to achieve therapeutic systemic exposure.

  • Example: Nitroglycerin is often given sublingually or IV rather than orally because of the first-pass effect.

Quick practice questions (reflections from the transcript)

• Overdose antidote administration route question:

  • Best route with 100% bioavailability: IV. Rationale: in overdose scenarios you want the antidote to reach systemic circulation fully and promptly; IV ensures 100% bioavailability, unlike oral, subcutaneous, or IM routes which have incomplete absorption.

• Drug A: weak base, pKa = 7.8. Which GI site would absorption be best for an oral dose?

  • Answer discussed in transcript: Jejunum (closest to the pKa among the options, with ~0.2 units difference). Rationale: weak bases absorb best in relatively alkaline environments where the nonpolar (unprotonated) form is favored (B). The jejunum is the most favorable site among the listed options due to its pH proximity to the drug’s pKa and its role in nutrient absorption.

  • Conceptual notes: Weak bases shift equilibrium toward nonpolar B form in alkaline environments; absorption is optimal where pH is high enough to favor nonpolar form but not so high as to cause complete deprotonation away from passive diffusion advantages.

Notable examples and concepts to remember

• Penicillin G example:

  • Penicillin G is unstable in gastric acid; oral administration leads to degradation by stomach acid, reducing bioavailability; typically given IM or IV to bypass gastric degradation.

• Insulin example:

  • Insulin is degraded by GI proteases; therefore, oral administration is ineffective; insulin is given by injection or other non-oral routes.

• P-glycoprotein and multi-drug resistance:

  • P-gp on the apical surface can actively pump absorbed drugs back into the GI lumen, reducing net absorption and contributing to variability in bioavailability; relevant in multi-drug resistance scenarios.

• Surface area and microstructure of the intestine:

  • The GI tract has enormous absorptive surface area (brush border, villi, microvilli); diseases that destroy these structures (IBD, celiac disease, gastroenteritis) decrease absorption due to reduced surface area.

• Diarrhea vs constipation effects on absorption:

  • Diarrhea decreases contact time with absorptive surfaces, reducing absorption.

  • Constipation increases contact time, potentially increasing absorption.

• Practical route distinction summary:

  • IV yields 100% bioavailability and bypasses first-pass metabolism.

  • PO is variable depending on solubility, stability, pH, surface area, contact time, and transporter activity, as well as first-pass metabolism by the liver.

• Core takeaway:

  • Bioavailability depends on multiple factors, and the route of administration critically determines how much drug reaches systemic circulation.

  • Understanding absorption mechanisms and the factors that influence them helps predict drug behavior, optimize dosing, and explain clinical choices (e.g., nitroglycerin delivery, overdose management).

Connections to foundational principles and real-world relevance

• Le Chatelier’s principle is used to explain how pH shifts (acidic vs basic environments) influence drug ionization and absorption.

• The Henderson–Hasselbalch concept underpins the relationship between pH, pKa, and the ratio of ionized to nonionized forms, which governs membrane permeability for weak acids and bases (implied in the discussion of HA ⇌ H+ + A− and BH+ ⇌ B + H+).

• Real-world relevance: choosing the route of administration to maximize desired bioavailability (e.g., sublingual nitroglycerin for rapid action, IV antidotes in overdose, IM/IV for penicillin G) is a practical application of pharmacokinetic principles.

• Ethical/practical implications: awareness of variable bioavailability informs dosing, monitoring, and equity in access to effective therapies; understanding first-pass effects reinforces the need for route-specific dosing and avoids ineffective regimens.

Key takeaways for exams

• Absorption basics: routes, membrane crossing mechanisms, and when absorption barriers matter most (e.g., IV bypasses barriers).

• Four absorption mechanisms with definitions and the B12 example for endocytosis.

• Major factors affecting absorption: pH (acidic vs alkaline environments), blood flow, surface area, contact time, and P-glycoprotein.

• Bioavailability (F): definition, IV = 100%, PO variable; the AUC-based formula to calculate F.

• First-pass metabolism and the hepatic portal system: impact on oral drugs; nitroglycerin as a classic example.

• Practical route decisions based on drug properties (solubility/instability) and patient condition (shock, GI disease).

• Practice question insights: route selection in emergencies and how pKa and pH influence site of absorption for weak bases.